ABSTRACT

Obesity can cause a decline in contractile function of skeletal muscle, thereby reducing mobility and promoting obesity-associated health risks. We reviewed the literature to establish the current state-of-knowledge of how obesity affects skeletal muscle contraction and relaxation. At a cellular level, the dominant effects of obesity are disrupted calcium signalling and 5′-adenosine monophosphate-activated protein kinase (AMPK) activity. As a result, there is a shift from slow to fast muscle fibre types. Decreased AMPK activity promotes the class II histone deacetylase (HDAC)-mediated inhibition of the myocyte enhancer factor 2 (MEF2). MEF2 promotes slow fibre type expression, and its activity is stimulated by the calcium-dependent phosphatase calcineurin. Obesity-induced attenuation of calcium signalling via its effects on calcineurin, as well as on adiponectin and actinin affects excitation–contraction coupling and excitation–transcription coupling in the myocyte. These molecular changes affect muscle contractile function and phenotype, and thereby in vivo and in vitro muscle performance. In vivo, obesity can increase the absolute force and power produced by increasing the demand on weight-supporting muscle. However, when normalised to body mass, muscle performance of obese individuals is reduced. Isolated muscle preparations show that obesity often leads to a decrease in force produced per muscle cross-sectional area, and power produced per muscle mass. Obesity and ageing have similar physiological consequences. The synergistic effects of obesity and ageing on muscle function may exacerbate morbidity and mortality. Important future research directions include determining: the relationship between time course of weight gain and changes in muscle function; the relative effects of weight gain and high-fat diet feeding per se; the effects of obesity on muscle function during ageing; and if the effects of obesity on muscle function are reversible.

Introduction

Obesity (see Glossary) is a major global health epidemic of the 20th and 21st centuries (Busutil et al., 2017; Hales et al., 2017). The World Health Organization defines obesity as abnormal or excessive fat accumulation that may impair health, indicated by a body mass index [BMI=mass (kg)/height2 (m2)]≥30 (Hales et al., 2017). Obesity has well-known metabolic effects, and leads to serious health complications by causing metabolic syndrome (see Glossary), cardiovascular disease, type 2 diabetes, and even increasing the risk of cancer (Muoio and Newgard, 2006). In addition to its metabolic effects, obesity can affect skeletal muscle function and thereby reduce mobility of obese individuals (Teasdale et al., 2013). There are two opposing trends. On the one hand, skeletal muscle of obese individuals has to work harder to move a greater body mass, which may result in a positive training effect (Garcia-Vicencio et al., 2016). On the other hand, obesity can also lead to a decrease in muscle mass and to lower muscle quality (Prado et al., 2008; Tallis et al., 2017). Overall, obesity is likely to lead to a reduced ability of skeletal muscle to maintain locomotor performance, which leads to lower mobility in obese individuals. Movement is important for maintaining a healthy body composition. Hence, the effects of obesity on the contractile performance of skeletal muscle may cause a negative obesity cycle: reduced mobility is likely to lead to lower activity levels and energy use, thereby causing further weight gain and consequently a reduction in quality of life (Busutil et al., 2017). Obesity accelerates the ageing process (Baumgartner et al., 2004), and it is particularly important to understand better the combined effects of obesity and ageing on skeletal muscle performance considering the ageing populations in many countries. Our aim here is to provide a summary of the cell signalling systems in skeletal muscle that are affected by obesity, and integrate these with current knowledge of the effects of obesity on skeletal muscle function and its interaction with ageing.

Muscle consists of different fibre types that determine metabolic and contractile properties (Fig. 1). Many of the effects of obesity on muscle function are mediated by its effect on fibre type composition. Muscle fibres are classified on the basis of their myosin heavy chain (MHC) isoform composition, which are broadly categorised into slow and fast fibres. In humans, these are slow type I and IIa fibres, which are poised towards oxidative metabolism with high fatigue resistance, but low shortening velocity, force and power production. At the other end of the spectrum are fast type IId/x and IIb fibres that are glycolytically poised with high shortening velocity, force and power production, but low fatigue resistance (Bassel-Duby and Olson, 2006). There is variation in the categorisation of fibre types and their mechanical properties among species (Berchtold et al., 2000; Schiaffino and Reggiani, 2011). However, while the details may change, the general categorisation of function into ‘slow’ and ‘fast’ fibre types remains valid.

Fig. 1.

Simplified description of the basic mechanisms that mediate muscle contraction and relaxation. Muscle contraction is initiated by a neural signal that stimulates specialised calcium channel proteins (dihydropyridine receptors, DHPR) situated in invaginations of the cell membrane projecting into the muscle cell, called t-tubules (I). Upon neural stimulation, DHPR physically interact with a second receptor, the ryanodine receptor (RyR), which is located in the membrane of the sarcoplasmic reticulum, an internal calcium store. When stimulated by DHPR, RyR releases calcium from the sarcoplasmic reticulum (II). Stimulation of DHPR also permits entry of extracellular calcium into the myocyte (not shown). Increased calcium concentrations inside the muscle cell lead to increased binding of calcium to troponin, a regulatory molecule that is associated with actin and myosin. Actin and myosin proteins represent the contractile apparatus of the muscle cell. Following calcium binding, troponin ‘unlocks’ tropomyosin, which in its unbound state prevents the interaction between actin and myosin (III). Once the inhibitory effect of tropomyosin is removed, myosin binds to actin via cross-bridges, which pull the myosin molecule along the actin molecule, thereby shortening the muscle fibre and causing muscle contraction. The sequence of events from nerve stimulation to contraction is termed excitation–contraction coupling. The actin/myosin-mediated contraction requires ATP, which is hydrolysed by myosin ATPase activity (IV). Calcium is re-sequestered into the sarcoplasmic reticulum by the sarco-endoplasmic reticulum ATPase (SERCA). The resultant decreases in calcium concentrations reverse the contraction process described above and cause muscle relaxation (V). SERCA hydrolyses ATP to pump calcium back into the sarcoplasmic reticulum. The basic mechanisms of contraction and relaxation are similar in fast and slow fibres, but the different muscle fibres possess different isoforms of the proteins involved such as myosin heavy and light chains, troponin and SERCA. In addition, there are some fibre type-specific proteins such as parvalbumin in fast fibres, which enhance calcium binding and thereby increase relaxation rates. More detailed descriptions of these mechanisms can be found in Berchtold et al. (2000), Gordon et al. (2000) and Gundersen (2011).

Fig. 1.

Simplified description of the basic mechanisms that mediate muscle contraction and relaxation. Muscle contraction is initiated by a neural signal that stimulates specialised calcium channel proteins (dihydropyridine receptors, DHPR) situated in invaginations of the cell membrane projecting into the muscle cell, called t-tubules (I). Upon neural stimulation, DHPR physically interact with a second receptor, the ryanodine receptor (RyR), which is located in the membrane of the sarcoplasmic reticulum, an internal calcium store. When stimulated by DHPR, RyR releases calcium from the sarcoplasmic reticulum (II). Stimulation of DHPR also permits entry of extracellular calcium into the myocyte (not shown). Increased calcium concentrations inside the muscle cell lead to increased binding of calcium to troponin, a regulatory molecule that is associated with actin and myosin. Actin and myosin proteins represent the contractile apparatus of the muscle cell. Following calcium binding, troponin ‘unlocks’ tropomyosin, which in its unbound state prevents the interaction between actin and myosin (III). Once the inhibitory effect of tropomyosin is removed, myosin binds to actin via cross-bridges, which pull the myosin molecule along the actin molecule, thereby shortening the muscle fibre and causing muscle contraction. The sequence of events from nerve stimulation to contraction is termed excitation–contraction coupling. The actin/myosin-mediated contraction requires ATP, which is hydrolysed by myosin ATPase activity (IV). Calcium is re-sequestered into the sarcoplasmic reticulum by the sarco-endoplasmic reticulum ATPase (SERCA). The resultant decreases in calcium concentrations reverse the contraction process described above and cause muscle relaxation (V). SERCA hydrolyses ATP to pump calcium back into the sarcoplasmic reticulum. The basic mechanisms of contraction and relaxation are similar in fast and slow fibres, but the different muscle fibres possess different isoforms of the proteins involved such as myosin heavy and light chains, troponin and SERCA. In addition, there are some fibre type-specific proteins such as parvalbumin in fast fibres, which enhance calcium binding and thereby increase relaxation rates. More detailed descriptions of these mechanisms can be found in Berchtold et al. (2000), Gordon et al. (2000) and Gundersen (2011).

Different fibre types have different isoforms of proteins involved in muscle excitation–contraction (see Glossary) and relaxation coupling. In addition to differences in the expression of myosin heavy chains, each fibre type may have different troponin and tropomyosin isoforms that translate the calcium signal to actin and myosin-mediated contraction. Fibre types can also differ in the sarco-endoplasmic reticulum ATPase (SERCA) isoforms that re-sequester calcium back into the sarcoplasmic reticulum to facilitate relaxation (Gordon et al., 2000; Gundersen, 2011). This variation ultimately leads to differences in metabolic and contractile function (James et al., 1995; Berchtold et al., 2000).

Obesity is associated with a shift to a faster muscle phenotype (Helge et al., 1999; Tanner et al., 2002; de Wilde et al., 2008; Stuart et al., 2013; Seebacher et al., 2017). Slow type I muscle fibres have greater insulin sensitivity and glucose uptake via the glucose transporter GLUT4 compared with fast fibres (Hickey et al., 1995; Bassel-Duby and Olson, 2006), so that fibre-type expression can be associated with metabolic as well as contractile characteristics of muscle (Zorzano et al., 2005; Gundersen, 2011; Wyckelsma et al., 2017). In addition, obesity-induced changes in contractile function may be associated with a reduction in myogenesis resulting from disruption of muscle satellite cell activation (Akhmedov and Berdeaux, 2013; D'Souza et al., 2015), changes in troponin isoforms that are involved in mediating cross-bridge cycling (see Glossary) (Ciapaite et al., 2015; Eshima et al., 2017), calcium handling and neuromuscular recruitment (Yoshida et al., 2012). However, these responses are not consistent across muscle groups, and experimentally established links between mechanisms and measures of contractility are lacking in an obesity model. Often, the responses to obesity are muscle specific, and the relatively small amount of literature means that understanding the effects of obesity on skeletal muscle contractile function is incomplete. It should be noted that changes in metabolic function can occur without fibre type transitions. For example, exercise training can lead to increases in metabolic capacities of muscle without changes in muscle fibre type (Rico-Sanz et al., 2003; Wyckelsma et al., 2017). Our aim here is to review the current state-of-knowledge, and to identify areas where research is currently lacking. We start by providing a mechanistic background and summarise the signalling processes that can mediate obesity-related changes in muscle fibre type (Fig. 2). A more thorough review of the signalling mechanisms that mediate muscle plasticity in general can be found in Hoppeler (2016). Changes in muscle fibre type are the most important mechanisms that alter contractile function as a result of obesity. The signalling processes we summarise in the first part of this Review therefore represent the mechanistic basis underlying changes in muscle contractile function in vivo and in isolated muscle preparations, which we review subsequently (Fig. 3). Lastly, we discuss the interaction between obesity and ageing, and identify future research directions.

Fig. 2.

Summary of regulatory pathways that are affected by obesity. The simplified diagram shows the major signalling pathways that are affected by obesity, and their downstream effect on muscle fibre type and contractile function. Obesity leads to increased insulin secretion and concentrations (green arrows indicate activation), and it inhibits (red lines) a number of processes that ultimately determine fibre type expression and thereby muscle function including metabolism, force production, power output and fatigue resistance. Green boxes indicate individual signalling molecules that overall promote slow fibre expression; red boxes indicate mechanisms that suppress slow fibre expression. DGK-δ, diacylglycerol kinase delta; Ca2+ signal, calcium signalling; AMPK, AMP-activated protein kinase; HDAC, histone deacetylase; MEF2, myocyte enhancer factor 2; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; SERCA, sarco-endoplasmic reticulum calcium ATPase.

Fig. 2.

Summary of regulatory pathways that are affected by obesity. The simplified diagram shows the major signalling pathways that are affected by obesity, and their downstream effect on muscle fibre type and contractile function. Obesity leads to increased insulin secretion and concentrations (green arrows indicate activation), and it inhibits (red lines) a number of processes that ultimately determine fibre type expression and thereby muscle function including metabolism, force production, power output and fatigue resistance. Green boxes indicate individual signalling molecules that overall promote slow fibre expression; red boxes indicate mechanisms that suppress slow fibre expression. DGK-δ, diacylglycerol kinase delta; Ca2+ signal, calcium signalling; AMPK, AMP-activated protein kinase; HDAC, histone deacetylase; MEF2, myocyte enhancer factor 2; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; SERCA, sarco-endoplasmic reticulum calcium ATPase.

List of abbreviations
     
  • AMP

    adenosine monophosphate

  •  
  • AMPK

    5′-adenosine monophosphate-activated protein kinase

  •  
  • ATP

    adenosine triphosphate

  •  
  • BMI

    body mass index

  •  
  • CaMK

    calmodulin-dependent protein kinase

  •  
  • CnA

    calcineurin

  •  
  • DAG

    diacylglycerol

  •  
  • DAK-δ

    diacylglycerol kinase delta

  •  
  • DHPR

    dihydropyridine receptor

  •  
  • EDL

    extensor digitorum longus

  •  
  • GLUT4

    glucose transporter 4

  •  
  • HDAC

    histone deacetylase

  •  
  • MEF2

    myocyte enhancer factor 2

  •  
  • MHC

    myosin heavy chain

  •  
  • NFAT

    nuclear factor of activated T-cells

  •  
  • PGC-1α

    peroxisome proliferator activated receptor gamma co-activator 1 alpha

  •  
  • PPARδ

    peroxisome proliferator activated receptor delta

  •  
  • ROS

    reactive oxygen species

  •  
  • RyR

    ryanodine receptor

  •  
  • SERCA

    sarco-endoplasmic reticulum ATPase

  •  
  • TGF-β1

    transforming growth factor beta 1

Fig. 3.

Summary of obesity-mediated effects on contractile function of skeletal muscle. Obesity can lead to increases in absolute force production and power output of weight-bearing muscles resulting from the increased demand (green box). However, when normalised to body mass, force production and power output decrease with obesity, leading to decreased muscle quality and fatigue resistance (red boxes). As a result, obese individuals have reduced mobility, exercise capacity and lipid oxidation (purple box).

Fig. 3.

Summary of obesity-mediated effects on contractile function of skeletal muscle. Obesity can lead to increases in absolute force production and power output of weight-bearing muscles resulting from the increased demand (green box). However, when normalised to body mass, force production and power output decrease with obesity, leading to decreased muscle quality and fatigue resistance (red boxes). As a result, obese individuals have reduced mobility, exercise capacity and lipid oxidation (purple box).

Signalling processes affected by obesity

Muscle contractile function is largely determined by calcium signalling within the muscle cell (Fig. 1), and the activity of proteins responsible for muscle contraction and relaxation (Berchtold et al., 2000; Gundersen, 2011; Gehlert et al., 2015), both of which differ between fibre types. Obesity affects muscle force production and power output by altering fibre type composition and disrupting calcium cycling (Funai et al., 2013, 2016; Seebacher et al., 2017). Obesity often leads to a slow-to-fast muscle fibre transition (Tanner et al., 2002; DeNies et al., 2014; Lee et al., 2015; Seebacher et al., 2017). A similar shift in fibre types occurs in response to high-sugar and high-fat diets in the absence of obesity (Hyatt et al., 2016). The high-fat diet-induced reduction in absolute and relative force produced by the fast extensor digitorum longus (EDL) muscle in mice was not accompanied by changes in proteins related to calcium cycling (ryanodine receptor, dihydropyridine receptor, parvalbumin, SERCA), but there was a decrease in the fast troponin isoform (Ciapaite et al., 2015; Eshima et al., 2017), which mediates calcium sensitivity (Ogut et al., 1999). Below, we summarise the mechanisms by which obesity can alter muscle fibre composition and muscle mass. There are several intersecting signalling pathways that are affected by obesity, principally centred on calcium signalling and 5′-adenosine monophosphate-activated protein kinase (AMPK) activity.

Glossary

Concentric muscle contraction

Force production while the muscle is shortening, e.g. shortening of the biceps while lifting an object.

Cross-bridge cycling

The binding between actin and myosin, leading to the shortening of the contractile part of the muscle cell, is termed a cross-bridge. Cross-bridge cycling is the repeated actin–myosin binding and detachment.

Eccentric muscle contraction

Force production while the muscle is lengthening, e.g. the quadriceps lengthens during walking while still producing power.

Excitation–contraction coupling

The process by which a neural signal leads to muscle contraction, which is mediated by calcium influx into the muscle cell.

Excitation–transcription coupling

Changes to gene transcription mediated by calcium influx into the muscle cell.

Isometric force

Force produced by a muscle of constant length.

Metabolic syndrome

A cluster of several medical conditions including obesity, high blood pressure, high blood glucose levels and high serum triglyceride levels.

Obesity

Abnormal or excessive fat accumulation that may impair health, indicated by a body mass index (BMI=mass [kg]/height2 [m2])≥30.

Stress

Stress is the force produced per muscle cross-sectional area.

Tetanus

Sustained isometric muscle contraction in response to high-frequency action potentials of the motor nerve, or electrical stimulation in vitro. A tetanus is characterised by the activation time or rate following stimulation, maximal tetanus force production, and a relaxation time or rate following stimulation.

Work loop technique

A specialised technique that measures in vitro muscle force production while the muscle is undergoing length changes. It is a more realistic indicator of in vivo muscle performance than isometric measures. The product of force and shortening velocity of the muscle is equal to the mechanical power produced.

Energy sensing: AMPK is a central signalling molecule in obesity

Obesity represents a disruption of whole-organism energy balance. In many animals, including humans, physiological signalling systems evolved in the context of high energy expenditure, often in environments with low nutrient and energy availability (Booth et al., 2002). Regulation of cellular energy balance, therefore, was a crucial evolutionary step in maintaining homeostasis within a fluctuating environment (Roustan et al., 2016). The principal regulator of energy balance, AMPK, is an ancient mechanism that evolved in prokaryotes and has maintained its function throughout evolution (Hardie et al., 2006, 2016). AMPK is activated by energy depletion, which in the cell is signalled by the decreasing ratio of the high-energy adenosine triphosphate (ATP) to the low-energy adenosine monophosphate (AMP) (Hardie et al., 2006; Cantó et al., 2009). ATP depletion resulting from muscle contraction during exercise, or from calorie restriction, for example, stimulates AMPK activity to facilitate catabolic processes and ATP synthesis (Narkar et al., 2008; Kristensen et al., 2015; Steinberg, 2018). In addition, activated AMPK itself can promote fast-to-slow muscle fibre transformation (Ljubicic et al., 2011), and thereby affect energy use (Irrcher et al., 2008; Steinberg, 2018) and contractile function (Gundersen, 2011).

Obesity suppresses AMPK activity (Steinberg et al., 2006), thereby reversing the actions of AMPK briefly described above and, among other effects, promoting fat deposition and a shift to fast muscle fibres. Obesity can also attenuate the exercise-stimulated activation of AMPK, thereby mediating exercise intolerance (Lee-Young et al., 2010). The obesity-induced suppression of AMPK activity may even be transferred between mother and offspring. Mesenchymal stem cells, which give rise to muscle cells and adipocytes, of human infants born to obese mothers have lower AMPK activity compared with those of infants from normal weight mothers (Du et al., 2010; Boyle et al., 2017).

AMPK interacts within complex signalling systems (Ross et al., 2016; Craig et al., 2017; Steinberg, 2018), and many of its actions are as yet poorly understood (Myers et al., 2017). However, with respect to muscle contractile function, the interaction between AMPK and histone deacetylases (HDAC) is of particular importance.

AMPK and histone acetylation

In eukaryotes, DNA molecules are condensed into nucleosomes by forming complexes with histone proteins. Access to DNA and regulation of gene expression is mediated by histone acetylation and methylation (Turner, 2012; Halsall and Turner, 2016). The balance between histone acetylation by histone acetylases and deacetylation by histone deacetylases (HDAC) modulates transcription (Wang et al., 2009). In mammals, class II HDACs are particularly important in determining muscle function by repressing expression of the transcription factor myocyte enhancer factor 2 (MEF2) (McGee and Hargreaves, 2011). MEF2, in conjunction with myogenic regulatory factors such as myogenin and MyoD (Molkentin et al., 1995), plays a central role in determining slow fibre expression (McGee and Hargreaves, 2004; Potthoff et al., 2007). An important role of AMPK in modulating muscle composition and function lies in lifting the suppressive effect of class II HDAC on MEF2 by mediating the export of HDAC from the nucleus (Salminen et al., 2016; Vilchinskaya et al., 2017). By supressing AMPK, obesity increases the effect of HDAC and reduces MEF2 expression (Fig. 4).

Fig. 4.

Schematic summary of how obesity affects muscle fibre type composition by suppressing AMPK activity and disrupting calcium cycling. AMP-activated protein kinase (AMPK) activity is increased by phosphorylation (pAMPK) in response to a reduction in the ratio between ATP and AMP resulting from energy expenditure during exercise, for example. AMPK activity induces a shift from fast to slow muscle fibres directly (I; green arrow indicates activation), and causes nuclear export of class II histone deacetylases (II; HDAC). HDAC suppress (dashed red line) transcription of the myocyte enhancer factor 2 (III; MEF2), which mediates the shift from fast to slow fibre types (IV). Nuclear export of HDAC lifts their suppressive effect, allowing MEF2 expression and fast to slow fibre type transformation (III, IV; green lines). Obesity inhibits (red lines) AMPK activity, thereby preventing the direct effects of AMPK on fibre type, the nuclear export of HDAC (II) and expression of MEF2 (III). Calcium release into the myocyte from extracellular sources or from stores in the sarcoplasmic reticulum is stimulated by muscular activity and exercise (blue arrows indicate activation; see also Fig. 1), and it activates calcineurin (V; CnA). Calcineurin causes the nuclear factor of activated T-cells (NFAT) to enter the nucleus (VI), where it stimulates transcription of MEF2 and slow fibre type expression (IV). Obesity disrupts calcium cycling (red lines), and calcineurin-mediated translocation of NFAT into the nucleus (VI; red line). Note that calcineurin also activates the transcriptional co-activator PGC-1α, which interacts with MEF2 to promote slow fibre type expression (details not shown, see main text).

Fig. 4.

Schematic summary of how obesity affects muscle fibre type composition by suppressing AMPK activity and disrupting calcium cycling. AMP-activated protein kinase (AMPK) activity is increased by phosphorylation (pAMPK) in response to a reduction in the ratio between ATP and AMP resulting from energy expenditure during exercise, for example. AMPK activity induces a shift from fast to slow muscle fibres directly (I; green arrow indicates activation), and causes nuclear export of class II histone deacetylases (II; HDAC). HDAC suppress (dashed red line) transcription of the myocyte enhancer factor 2 (III; MEF2), which mediates the shift from fast to slow fibre types (IV). Nuclear export of HDAC lifts their suppressive effect, allowing MEF2 expression and fast to slow fibre type transformation (III, IV; green lines). Obesity inhibits (red lines) AMPK activity, thereby preventing the direct effects of AMPK on fibre type, the nuclear export of HDAC (II) and expression of MEF2 (III). Calcium release into the myocyte from extracellular sources or from stores in the sarcoplasmic reticulum is stimulated by muscular activity and exercise (blue arrows indicate activation; see also Fig. 1), and it activates calcineurin (V; CnA). Calcineurin causes the nuclear factor of activated T-cells (NFAT) to enter the nucleus (VI), where it stimulates transcription of MEF2 and slow fibre type expression (IV). Obesity disrupts calcium cycling (red lines), and calcineurin-mediated translocation of NFAT into the nucleus (VI; red line). Note that calcineurin also activates the transcriptional co-activator PGC-1α, which interacts with MEF2 to promote slow fibre type expression (details not shown, see main text).

MEF2 activity is sensitive to calcium signalling, and it promotes formation of slow-twitch type I muscle fibres that maintain higher calcium concentrations compared with fast-twitch fibres (McKinsey et al., 2002; Bassel-Duby and Olson, 2006). MEF2 is regulated by class II HDAC4 and HDAC5, which form a complex with HDAC3 to decrease slow muscle fibre gene expression by repressing MEF2 activity (Liu et al., 2005; Cohen et al., 2015). Conversely, slow fibre expression is stimulated by translocation of HDAC4 from the nucleus to the cytoplasm, thereby releasing the block on MEF2 (Liu et al., 2005). Calmodulin-dependent protein kinase (CaMK) and AMPK phosphorylate HDAC, and phosphorylated HDACs bind to chaperone protein 14-3-3 within the nucleus and are exported via a complex with the transport protein CRM1 (Grozinger and Schreiber, 2000; McGee and Hargreaves, 2010). Translocation of HDAC4 was blocked by inhibiting CaMK. In contrast, export of HDAC from the nucleus was stimulated by calcium signalling and energy imbalance, which activate CaMKII and AMPK, respectively (Liu et al., 2005; McGee and Hargreaves, 2011). Inhibition of AMPK also decreased expression of myogenin and myogenesis by reducing phosphorylation of HDAC5 and thereby increasing its repressive effects (Fu et al., 2013).

Calcium signals are disrupted by obesity

Calcium plays an important role in signalling changes to gene expression and muscle phenotype in addition to facilitating muscle contraction and relaxation (Fig. 1). For example, the calcium-dependent phosphatase calcineurin is stimulated by calcium release in the myocyte. Calcineurin is activated by prolonged low-frequency firing of motor neurons leading to low-amplitude calcium waves typical of slow muscle fibres (Michel et al., 2007). Calcineurin stimulates MEF2 and increases in slow fibre expression (Chin et al., 1998). Calcineurin stimulation led to increased transcription of slow type I fibre-specific genes, such as myoglobin and slow troponin isoforms (Bassel-Duby and Olson, 2006; Michel et al., 2007). Similarly, the endurance exercise-stimulated activation of MEF-2, which led to fast-to-slow fibre type transition and increased oxidative capacity, was dependent on calcineurin (Wu et al., 2001). Calcium release therefore mediates contraction and relaxation (excitation–contraction coupling), and leads to regulating gene expression (excitation–transcription coupling; see Glossary) and muscle phenotype (Michel et al., 2007).

Upon activation, calcineurin dephosphorylates the nuclear factor of activated T-cells (NFAT), leading to the translocation of NFAT from the cytoplasm to the nucleus (McGee and Hargreaves, 2004) (Fig. 4). In the nucleus, NFAT associates with other transcription factors to activate specific target genes, including MEF-2 (Wu et al., 2001). Overexpression of calcineurin led to suppression of fast contractile isoforms (Martins et al., 2012). In the reverse process, phosphorylation of skeletal muscle NFAT resulted in its nuclear export (Shen et al., 2007) and inhibition of NFAT-mediated increases in slow MHC gene expression (Jiang et al., 2006). Muscle phenotypes and contractile function therefore depend on the balance between MEF2 repression by HDACs and activation via calcineurin (McGee and Hargreaves, 2004). In addition, calcineurin regulates skeletal muscle mass (Michel et al., 2004; Hudson and Price, 2013), so that obesity-induced decreases in muscle mass could be partially explained by disrupted calcium signalling.

Obesity and ageing can disrupt calcium signalling by promoting excess production of reactive oxygen species (ROS) leading to oxidative stress (Espinosa et al., 2016; Di Meo et al., 2017). For example, oxidative stress can impair SERCA function, and induce calcium leak from the sarcoplasmic reticulum by its effect on ryanodine receptors (Matsunaga et al., 2003; Baumann et al., 2016). Disrupted calcium signalling could also result from lower sensitivity to motor stimulation in obese individuals (Maffiuletti et al., 2011). In addition, differential expression of muscle-specific structural actinin proteins can be associated with obesity (Insenser et al., 2012), and actinin is involved in fibre type transformation by mediating repression of calcineurin via calsarcins (Frey et al., 2008; Seto et al., 2013). Calsarcins (also known as Myoz) are associated with α-actinin (Frey et al., 2000), and calsarcin-1 suppressed calcineurin activity and thereby reduced slow fibre type expression (Lomonosova et al., 2016). Mice with a calsarcin-1 knock-out had excessive slow fibre expression (Frey et al., 2004), and mice deficient in calsarcin-2 had lower body mass, exhibited a shift from fast to slow muscle fibres, and showed improved endurance exercise performance (Frey et al., 2008). Similarly, actinin 3 deficiency increased calcineurin activity and hence slow fibre type expression and endurance exercise capacity in human and mouse muscle (Seto et al., 2013). Actinin 3 knock-out mice expressed greater slow type I muscle fibres, and gained less weight than wild-type mice. However, a naturally occurring null polymorphism in the actinin 3 gene did not affect body mass index or obesity in humans (Houweling et al., 2017).

Calcineurin interacts with PGC-1α

The peroxisome-proliferator activated receptor gamma co-activator-1α (PGC-1α) is a master controller of metabolism with pronounced influences on skeletal muscle. PGC-1α is positively associated with oxidative energy metabolism and transition to slow muscle fibres (Wu et al., 1999; Lin et al., 2002), and is induced by endurance exercise and in response to cold (Egan et al., 2010; Little et al., 2010; Philp et al., 2011; Smiles and Camera, 2015). In addition, calcineurin induced the expression of PGC-1α and its target, the nuclear receptor peroxisome proliferator activated receptor δ (PPARδ) in mice (Long et al., 2007). PGC-1α co-activates PPARδ, which promotes type I fibre expression and endurance performance, and genetically increased PPARδ phenotypes possessed resistance to obesity even without exercise (Wang et al., 2003). PGC-1α also induces MEF2 (Puigserver, 2005), and there is a positive feedback loop between PGC-1α and MEF2: when co-activated by PGC-1α, MEF2 binds to the PGC-1α promoter to stimulate its expression (Handschin et al., 2003). Hence, there is a link between muscle calcium and PGC-1α signalling, which can be disrupted by the effects of obesity on calcium cycling in the myocyte. Muscle PGC-1α expression is also regulated by AMPK (Jäger et al., 2007; Irrcher et al., 2008; Lira et al., 2010), which is sensitive to obesity as described above. Increased PGC-1α expression also protects from sarcopenia in ageing (Wenz et al., 2009), and from muscle disuse atrophy (Sandri et al., 2006; Cannavino et al., 2015). The association between obesity and ageing, which we discuss in more detail below, may therefore be explained at least partly by calcineurin–AMPK–PGC-1α signalling.

Consequences of obesity-induced decreases in adiponectin and insulin sensitivity

Obesity reduces the secretion of adiponectin, a hormone secreted in adipocytes, as well as its receptors, AdipoR1 and AdipoR2, which together influence metabolism, insulin sensitivity and muscle fibre type expression (Yang et al., 2001; Pérez et al., 2016). Adiponectin and its receptors mediate extracellular calcium influx into the muscle cell, which leads to subsequent activation of metabolic regulators such as the NAD+-dependent histone deacetylase (SIRT1), AMPK and PGC-1α (Yamauchi et al., 2002; Iwabu et al., 2010). Adiponectin thereby represents an additional signalling mechanism that is negatively affected by obesity, and which has a pronounced influence on muscle fibre types by influencing calcium signalling. Obesity leads to increased visceral adipose tissue deposits, which display disrupted secretions of adiponectin (Pérez et al., 2016), as well as increased production of inflammatory cytokines and chemokines that can decrease production of contractile proteins in myotubes, and affect muscle fibre size distribution (Pellegrinelli et al., 2015). Adiponectin can be produced in muscle cells directly, and mice with a knock-out of muscle adiponectin showed lower peak tetanic force, but no effect on fatigue resistance (Krause et al., 2008).

Obesity-induced decreases in adiponectin led to decreased insulin sensitivity, but increased circulating insulin levels (Kadowaki et al., 2006; Gaur et al., 2017). Increased insulin levels inhibit AMPK activity in muscle and thereby slow fibre type expression (Valentine et al., 2014). It is possible, therefore, that the observed shift from slow to fast muscle fibres in obese individuals is partly caused by an insulin-mediated decrease in AMPK activity. Insulin responsiveness and metabolic rates correlate positively with the proportion of type I fibres; fewer type I fibres and more mixed type IIa fibres are typical in metabolic syndrome (Stuart et al., 2013).

In the insulin-resistant state, ligands of transforming growth factor beta 1 receptor (TGF-β1) are up-regulated (Watts et al., 2013). One of these ligands, myostatin, was up-regulated during obesity in mice (Allen et al., 2008b) but not in humans (Watts et al., 2013). However, altered concentrations and phosphorylation of the TGF-β1 signal transducers Smad2, Smad3 and Smad4 during obesity in humans was associated with a decrease in transcription of MyoD, a muscle regulatory factor that promotes muscle growth (Watts et al., 2013). Reduced muscle mass in obesity is therefore at least partly mediated through the TGF-β1 pathway. In addition, obesity-induced insulin resistance and type 2 diabetes are associated with increased levels of diacylglycerol (DAG), a precursor to triglycerides, and reduced diacylglycerol kinase delta (DAK-δ) activity (Chibalin et al., 2008). DAK-δ are lipid kinases that break down DAG, and are associated with fat deposition and obesity (Chibalin et al., 2008). DAK-δ deficiency in mice impaired AMPK activity, lipid metabolism and muscle contractile function (Jiang et al., 2016), indicating that disrupted lipid metabolism in obese individuals leads to impaired muscle function and locomotor activity via AMPK signalling (Fig. 1).

In summary, obesity influences muscle contractile function via a range of signalling pathways, but its most dominant influence is via disrupted calcium cycling and reduced AMPK activity, which leads to slow-to-fast fibre type transformation. Below, we review the consequences of these molecular changes on muscle function in vivo and in isolated muscle preparations.

Effects of obesity on in vivo skeletal muscle function in humans

Obesity can affect muscle isometric, concentric and eccentric force (see Glossary) (Fig. 3) (Maffiuletti et al., 2013; Tomlinson et al., 2016; Bollinger, 2017). Isometric strength is needed for postural control, but during locomotion and functional tasks (e.g. walking, rising from a chair, and ascending stairs) muscle undergoes length changes and can perform a range of functions such as powering locomotion, acting as a brake, spring or strut (Dickinson et al., 2000). Hence, isometric measurements (i.e. measurements taken at a constant muscle length) are not necessarily good approximations for muscle power, which necessitates length changes. The necessity to generate both muscular strength and power have important biomechanical implications. Obesity-induced changes in contractile performance could therefore have serious biomechanical consequences for many tasks performed during daily living.

The effect of obesity is not uniform across muscles or contractile modalities, and anatomical location and in vivo function of skeletal muscle can influence changes in mechanical performance (Maffiuletti et al., 2013; Bollinger, 2017). There are three important indicators of muscle function that have been reported in the literature: (1) absolute force or power-producing capacity of a muscle group; (2) force or power normalised to body mass or fat free mass; and, to a lesser extent, (3) muscle quality, defined as force or power normalised to muscle mass. Obesity can be associated with an increase in the capacity of weight-bearing skeletal muscles to produce absolute force and power for locomotion and postural control (e.g. knee extensor and trunk musculature) (Hulens et al., 2001; Rolland et al., 2004; Lafortuna et al., 2005; Maffiuletti et al., 2007; Abdelmoula et al., 2012; Tomlinson et al., 2014), but it does not affect performance of other skeletal musculature (Hulens et al., 2001; Rolland et al., 2004; Lafortuna et al., 2005). Excess body mass of obese individuals increases the demand placed on the skeletal muscles during standing and locomotion, and this can lead to a beneficial training adaptation in some muscles (Hulens et al., 2001; Lafortuna et al., 2005). However, obesity does not always lead to changes in absolute force and power (Pescatello et al., 2007; Gadducci et al., 2017). Discrepancies between studies at least partly relate to the specific muscle examined, participant physical activity levels, age, and duration and magnitude of obesity (i.e. duration and extent of overloading), which can affect the scope and magnitude of mechanistic responses. Importantly, obesity has been associated with a reduction in skeletal muscle protein synthesis (Akhmedov and Berdeaux, 2013), which would substantially reduce any positive adaptation evoked via an overload stimulus. Functional impairment associated with obesity (Pataky et al., 2013) and the resultant modified movement strategy (Runhaar et al., 2011) may place greater demand on some muscles, which can contribute to disparity in adaptation between muscles (Bollinger, 2017).

Muscles of obese individuals may produce greater absolute force or power when performing knee extensions or similar movements, but when normalised to body mass muscle performance is significantly lower than in lean individuals (Hulens et al., 2001; Lafortuna et al., 2005; Maffiuletti et al., 2007; Abdelmoula et al., 2012). These dynamics explain the lower performance of obese individuals in functional movement tasks, demonstrating that any improvement in absolute skeletal muscle performance does not counterbalance the substantial increase in body inertia. Similarly, the benefit of greater absolute muscle strength and power in obese individuals usually disappears when performance is normalised to fat free mass or muscle mass (Blimkie et al., 1990; Lafortuna et al., 2005; Maffiuletti et al., 2007). However, this is not always the case (Hulens et al., 2001; Hilton et al., 2008; Abdelmoula et al., 2012; Rahemi et al., 2015; Choi et al., 2016), and the effect of obesity on the intrinsic force-producing capacity of skeletal muscle is unresolved (Maffiuletti et al., 2013; Bollinger, 2017).

Advantages of isolated muscle preparations

Measuring the effect of obesity on isolated skeletal muscle function (Table 1) can enhance understanding of the mechanisms underpinning altered in vivo muscle performance. Most significantly, an isolated skeletal muscle approach permits direct assessment of the effects of obesity on muscle quality (force or power normalised to muscle size). Understanding obesity-associated changes in muscle quality is important, as obesity appears to result in larger muscles of lower quality (i.e. less contractile force per unit of cross-sectional area and lower power output per unit of muscle mass), which has the same absolute force and power output of smaller muscles in lean individuals (Tallis et al., 2017). This reduction in muscle quality results in two significant limitations: firstly, although obesity may not decrease absolute muscle performance, muscles of obese individuals are responsible for transporting and controlling the movement of a larger body mass. Secondly, larger muscles will contribute to an already elevated body mass, and therefore further increase the force required to overcome body inertia (Tallis et al., 2017). In vivo assessments of muscle quality in humans have estimated the volume of a muscle group using computed axial tomography scans (Blimkie et al., 1990), magnetic resonance imaging (Hilton et al., 2008), or ultrasound (Choi et al., 2016). The variation in assessment method may have contributed to the ambiguity with respect to the effect of obesity on muscle quality reported in previous in vivo studies. In an isolated skeletal muscle model, the mass of the contractile tissue can be measured directly to achieve greater accuracy in the assessment of muscle quality. Furthermore, in vivo assessments of muscle function consider the effect of obesity on whole muscle groups. Considering that each muscle varies in its form, function and fibre type distribution, in vivo methods are less suitable for determining muscle-specific effects.

Table 1.

Summary of studies examining the effect of obesity on isolated skeletal muscle contractile function

Summary of studies examining the effect of obesity on isolated skeletal muscle contractile function
Summary of studies examining the effect of obesity on isolated skeletal muscle contractile function

An isolated skeletal muscle approach allows the examination of direct effects of obesity on muscle contractile function. Obesity-related changes in muscle function can be caused by changes in neural activation (Blimkie et al., 1990). An isolated muscle preparation can be stimulated directly to produce a contractile response, so that the influence of neural factors is removed. In addition, electrical stimulation results in complete muscle activation so that contractile responses are not confounded by motivation or central inhibition. Similarly, treatment conditions such as the diet of the animal model, drugs administered to the muscle, and thermal conditions can be controlled much more tightly in an isolated muscle preparation.

The effect of obesity on in vitro muscle function

Comparing studies examining the effect of obesity on the contractile performance of isolated skeletal muscle is challenging, given the varied methodological approaches that likely contribute to a lack of consistency amongst findings (Table 1). The muscle examined, contractility mode, feeding duration, diet composition and temperature at which performance is assessed appear to have profound effects on the obesity response. Ambiguities remain even though studies share similarity in the assessment of maximal isometric tetanus (see Glossary) force, and the use of rodent soleus and EDL muscles to represent slow and fast fibre types, respectively (Ayre and Hulbert, 1996; Ciapaite et al., 2015; Bott et al., 2017; Eshima et al., 2017; Tallis et al., 2017).

Despite evidence of a reduction in isometric stress (force relative to muscle cross-sectional area; see Glossary) of mouse soleus, and elevated isometric activation and relaxation times of both the EDL and soleus (Warmington et al., 2000), skeletal muscle contractile responses to genetically induced obesity are limited (van Lunteren, 1996; Matsakas et al., 2015). Moreover, obesity-associated changes in contractile responses and their underpinning mechanisms differ between genetic obesity models and dietary-induced obesity models (Matsakas et al., 2015). Typically, genetically induced obesity is associated with decreased muscle mass (Stickland et al., 1994; Warmington et al., 2000; Kemp et al., 2009). In contrast, obesity induced by high-fat diets results in either no change (Ciapaite et al., 2015; Eshima et al., 2017) or an increase in muscle mass (Ciapaite et al., 2015; Tallis et al., 2017). Diet-induced obesity is more relevant to the potential effects of the obesity epidemic in humans, therefore we will focus this Review on diet-induced obesity models.

Diet-induced obesity is commonly associated with a reduction in isometric stress, and changes in the rate of relaxation of skeletal muscle (Ayre and Hulbert, 1996; Ciapaite et al., 2015; Eshima et al., 2017; Tallis et al., 2017). However, available data are inconsistent. Unlike for humans, there are no clear criteria to classify obesity in rodents. There is large variability in the duration of high-fat diet administration in the literature (3–16 weeks; Table 1). Unsurprisingly, the severity of the effects appears to increase with feeding duration, and the shortest time course (3 weeks of high-fat diet consumption) had little effect on contractile performance (Thomas et al., 2014). Animal models with muscles that have a faster phenotype prior to high-fat diet consumption become more oxidative after treatment (Trajcevski et al., 2013; Ciapaite et al., 2015; Eshima et al., 2017). The obesity-induced change in muscle fibre type and metabolic profile may be affected by feeding duration. Short-term high-fat diet may cause an increase in slow MHC isoform and proteins involved with oxidative phosphorylation as a positive adaption to elevated lipid accumulation, but in the longer term genes involved in oxidative phosphorylation are down-regulated (de Wilde et al., 2008). The potential for a dose–response relationship between feeding duration and contractile performance is yet to be explicitly explored.

It is likely that the effects of obesity vary among different dietary fat sources (Mizunoya et al., 2013). For example, consumption of a high-fat palm oil diet led to a reduction in isometric twitch and tetanus force when normalised to muscle mass, but this result was not mirrored in a group receiving a high-fat lard diet for the same duration (Ciapaite et al., 2015). In many studies, diet quality is confounded by obesity. A common approach in the literature is to expose an obese treatment group (mice or other models) to a high-fat diet, while the control group is kept on a regular, low-fat diet (DeNies et al., 2014; Nitti et al., 2016). However, high-fat diet per se can have physiological effects in the absence of obesity (Bhagat et al., 2015; Hyatt et al., 2016; Burke et al., 2017). Hence, the effect of obesity may be masked or altered by different diet qualities. In humans, a high-fat diet is often associated with obesity so that this treatment combination may be relevant. However, hypotheses and interpretations of data should consider the potentially confounding effects of altering two experimental variables (diet quality and body mass) concurrently.

It is clear from the evidence that obesity effects are not uniform across muscles (Table 1). However, the outlined methodological discrepancies present a challenge when trying to establish the nature of a muscle-specific effect. For example, there was an obesity-induced decrease in the relative maximal isometric force of mouse soleus muscle (Ciapaite et al., 2015), which was not seen in other studies on mouse or rat soleus (Ayre and Hulbert, 1996; Bott et al., 2017; Tallis et al., 2017). Similarly, an obesity-induced reduction in the maximal isometric stress of mouse EDL in the studies by Tallis et al. (2017) and Eshima et al. (2017) was not found in other studies (Ayre and Hulbert, 1996; Ciapaite et al., 2015; Bott et al., 2017). Such discrepancies may further relate to a difference in the temperature at which measurements were taken (James, 2013). Isometric force, activation time, relaxation time and mechanical power are improved at higher test temperatures, and optimal performance in mice occurs at around 35–40°C, which reflects the common in vivo temperature range (James et al., 2015). Test temperatures vary widely in the literature, from 20 to 37°C in rodents, or have not been reported (Table 1). Studies that have examined contractility in multiple muscles provide clearer evidence of a muscle-specific effect (Ayre and Hulbert, 1996; Ciapaite et al., 2015; Bott et al., 2017; Tallis et al., 2017). Interestingly, 5 weeks of high-fat diet (HFD) feeding caused a greater reduction in the contractile performance of relatively slow twitch soleus compared with relatively fast twitch EDL (Ciapaite et al., 2015). This result is contradictory to evidence using a 16-week HFD feeding regime (Tallis et al., 2017). It has been considered that the muscle-specific effect may be confounded by feeding duration as well as possibly being influenced by not only fibre type, but also anatomical location and in vivo function (Tallis et al., 2017), the latter of which is likely to be modified by a greater body mass.

A focus on fixed length isometric contraction may present limitations of this body of work when considered in relation to muscle activity in vivo. Locomotion in humans and other animals relies on dynamic muscle activity, where muscles that generate or absorb net power undergo cycles of length change while active (Josephson, 1993; James et al., 1996). Isometric measurements of force production are poor predictors of force production during concentric/eccentric contraction. Dynamic muscle activity can be determined using the work loop technique (see Glossary) to determine power during cycles of muscle lengthening and shortening (Josephson, 1993; Caiozzo, 2002). Use of the work loop technique is, as yet, relatively rare in studies relating to obesity. However, obesity may elicit a reduction in power output normalised to locomotor muscle mass in zebrafish and mice (Seebacher et al., 2017; Tallis et al., 2017), although absolute muscle power output was not affected in mice (Tallis et al., 2017). Interestingly, the absolute isometric force of isolated soleus was greater in obese mice, supporting previous human work suggesting a training adaptation for weight-bearing muscles (Tallis et al., 2017). This finding implies that obesity induces a contractile-specific adaptation in muscle function, with reduced plasticity in dynamic power-producing muscle activity. In addition, increases in absolute force and power are proportionally less than the magnitude of body mass increase so that locomotor performance is still likely to decrease with obesity (Seebacher et al., 2017; Tallis et al., 2017).

Most locomotor and functional tasks of daily living require sustained muscle contractility, so that muscle fatigue can be an important constraint on locomotion and activity (Allen et al., 2008a). The effects of obesity on muscle fatigue resistance are not well resolved (Maffiuletti et al., 2013; Tallis et al., 2017), and the available data on fatigue resistance in vivo are equivocal (Maffiuletti et al., 2007, 2008; Mayer et al., 2012; Paolillo et al., 2012; Minetto et al., 2013). As above, discrepancies between studies can be attributed largely to variation in experimental design (i.e. differences in muscle groups tested, mode of exercise, age and gender). In isolated muscle models, the effect of obesity on fatigue resistance changes with contraction type and muscle group (Table 1). Fatigue resistance has been assessed via repeated tetani at low and high simulation frequencies, or by subjecting isolated muscle to repeated maximal work loops (Table 1). Generally at the muscle level, fatigue resistance in obese individuals is unchanged or reduced when muscle is stimulated to produce maximal or near-maximal force or power (Thomas et al., 2014; Seebacher et al., 2017; Tallis et al., 2017), indicating that the obesity-associated reduction in sustained activity in vivo is not wholly related to an increase in force requirement to overcome an elevated body weight.

Contribution of obesity to muscle ageing

There is a parallel between the physiological changes associated with ageing and obesity; obesity can produce a physiological phenotype typical of ageing even in relatively young individuals (Pérez et al., 2016). Obesity-related changes may also exacerbate the ageing process (Baumgartner et al., 2004). Increasing age is associated with substantial changes in body composition, and in humans maximal fat mass is reached by 60–70 years of age (Villareal et al., 2005). Moreover, there is a global trend for an increased prevalence of obesity in older adults (Samper-Ternent and Snih, 2012), and it is estimated that around 40% of older (>60 years) Americans (USA) are obese (Hales et al., 2017). In humans, ageing is associated with a reduction in isometric and concentric muscle function, but eccentric performance appears to be well maintained (Doherty, 2003; Raj et al., 2010). The synergistic impacts of obesity and ageing may exacerbate the risk of morbidity and mortality. However, the evidence evaluating the effects of obesity on in vivo muscle function in older adults is limited and equivocal (Maffiuletti et al., 2013). The small number of studies in this area have been reviewed recently (Maffiuletti et al., 2013; Tomlinson et al., 2016; Bollinger, 2017), and in general the effects of obesity in the elderly mirror those in younger obese individuals, although older individuals may be disproportionately worse affected at a functional level (Baumgartner et al., 2004).

Obesity may result in reduced absolute strength in the elderly (Zoico et al., 2004), although these data need to be normalised to physical activity levels (Rolland et al., 2004). Reduction in absolute strength in the elderly may be partly explained by a synergistic reduction in protein synthesis in obesity and ageing that limits the ability of muscle to adapt to an elevated body mass (Tomlinson et al., 2016). The single study to date that measured the synergistic effects of ageing and obesity on isolated skeletal muscle function (Bott et al., 2017) demonstrated that obesity reduced the isometric activation and relaxation times in 33 week old mice. However, these animals were relatively young given that rodents, and in particular C57BL/6J strain mice, tend to have a lifespan in excess of 100 weeks (Kunstyr and Leunenberger, 1975). It is not clear if the increased functional impairment of older and obese individuals, compared with older and lean individuals (Zoico et al., 2004; Rolland et al., 2009), results from an accelerated reduction in muscle function, or the greater demand placed on already weakened muscles due to the elevated body mass. Given that both obesity and ageing share some common mechanistic characteristics, such as chronic inflammation, reduced protein synthesis, denervation and change in calcium kinetics (Navarro et al., 2001; Akhmedov and Berdeaux, 2013; Pérez et al., 2016; Bollinger, 2017), obesity has the potential to exacerbate skeletal muscle ageing. In addition to these common responses of ageing and obesity, there may be opposing effects on factors that mediate fibre type composition, given that obesity is associated with a faster fibre type composition (Bollinger, 2017) and ageing with slower fibre types (Deschenes, 2004).

Future directions

In summary, the principal effects of obesity are a shift in muscle fibre type that is mediated by disrupted calcium cycling and energy sensing, and which leads to altered in vivo and in vitro muscle function. Contradictory findings from in vitro and in vivo studies are at least partly owing to lack of standardisation in methodology. Based on our review of the literature we suggest the following to be important areas for future work.

Determining the effects of obesity on eccentric muscle function

Eccentric muscle performance is important in movement control and it is therefore fundamental in tasks of daily living (e.g. stair descent, postural control) (Choi, 2016). The elevated body weight of obese individuals is likely to increase the demand on this form of muscle action and any reduction in performance could result in functional impairment and increased injury risk.

Measuring the time course of effects of feeding on a high-fat diet on in vivo and isolated skeletal muscle performance

There is some evidence demonstrating that longer duration feeding on a high-fat diet increases the severity of the effects of obesity (Table 1). The longest feeding duration used in the literature is 16 weeks and it is likely that the magnitude of the resultant effects could be exacerbated with even longer duration feeding. Future work should examine muscle-specific mechanisms resulting in the change in muscle function across a range of feeding durations. In addition, as pointed out above, experiments should explicitly differentiate between the relative effects of high-fat diet per se and obesity.

Assessing the contribution of obesity to skeletal muscle ageing

In vivo evidence in this area is limited and ambiguous. There are a number of studies examining the effect of ageing on isolated skeletal muscle contractility, but the contribution of obesity is as yet unresolved. Understanding any synergies between the effects of ageing and obesity are particularly important considering that adiposity increases with age.

Determining whether the effects of obesity on skeletal muscle performance are reversible

Ayre and Hulbert (1996) demonstrated that a 6 week dietary intervention effectively reversed detrimental changes in muscle function induced by a diet deficient in essential fatty acids. In contrast, and despite improvement in metabolic scope, a similar dietary intervention failed to reverse obesity-induced changes in skeletal muscle function and fibre type expression (Seebacher et al., 2017). Future work should examine the effectiveness of caloric restriction, exercise, and their combination, on reversing the detrimental effects of obesity on skeletal muscle performance.

Footnotes

Funding

This work was funded by Coventry University and an Australian Research Council Grant to F.S.

References

Abdelmoula
,
A.
,
Martin
,
V.
,
Bouchant
,
A.
,
Walrand
,
S.
,
Lavet
,
C.
,
Taillardat
,
M.
,
Maffiuletti
,
N. A.
,
Boisseau
,
N.
,
Duché
,
P.
and
Ratel
,
S.
(
2012
).
Knee extension strength in obese and nonobese male adolescents
.
Appl. Physiol. Nutr. Metab.
37
,
269
-
275
.
Akhmedov
,
D.
and
Berdeaux
,
R.
(
2013
).
The effects of obesity on skeletal muscle regeneration
.
Front. Physiol.
4
,
1
-
12
.
Allen
,
D. G.
,
Lamb
,
G. D.
and
Westerblad
,
H.
(
2008a
).
Skeletal muscle fatigue: cellular mechanisms
.
Physiol. Rev.
88
,
287
-
332
.
Allen
,
D. L.
,
Cleary
,
A. S.
,
Speaker
,
K. J.
,
Lindsay
,
S. F.
,
Uyenishi
,
J.
,
Reed
,
J. M.
,
Madden
,
M. C.
and
Mehan
,
R. S.
(
2008b
).
Myostatin, activin receptor IIb, and follistatin-like-3 gene expression are altered in adipose tissue and skeletal muscle of obese mice
.
Am. J. Physiol. Endocrinol. Metab.
294
,
E918
-
E927
.
Ayre
,
K. J.
and
Hulbert
,
A. J.
(
1996
).
Effects of changes in dietary fatty acids on isolated skeletal muscle functions in rats
.
J. Appl. Physiol.
80
,
464
-
471
.
Bassel-Duby
,
R.
and
Olson
,
E. N.
(
2006
).
Signaling pathways in skeletal muscle remodeling
.
Annu. Rev. Biochem.
75
,
19
-
37
.
Baumann
,
C. W.
,
Kwak
,
D.
,
Liu
,
H. M.
and
Thompson
,
L. D. V.
(
2016
).
Age-induced oxidative stress: how does it influence skeletal muscle quantity and quality?
J. Appl. Physiol.
121
,
1047
-
1052
.
Baumgartner
,
R. N.
,
Wayne
,
S. J.
,
Waters
,
D. L.
,
Janssen
,
I.
,
Gallagher
,
D.
and
Morley
,
J. E.
(
2004
).
Sarcopenic obesity predicts instrumental activities of daily living disability in the elderly
.
Obes. Res.
12
,
1995
-
2004
.
Berchtold
,
M. W.
,
Brinkmeier
,
H.
and
Müntener
,
M.
(
2000
).
Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease
.
Physiol. Rev.
80
,
1215
-
1265
.
Bhagat
,
R.
,
Fortna
,
S. R.
and
Browning
,
K. N.
(
2015
).
Exposure to a high fat diet during the perinatal period alters vagal motoneurone excitability, even in the absence of obesity
.
J. Physiol. (Lond)
593
,
285
-
303
.
Blimkie
,
C. J. R.
,
Sale
,
D. G.
and
Bar-Or
,
O.
(
1990
).
Voluntary strength, evoked twitch contractile properties and motor unit activation of knee extensors in obese and non-obese adolescent males
.
Eur. J. Appl. Physiol.
61
,
313
-
318
.
Bollinger
,
L. M.
(
2017
).
Potential contributions of skeletal muscle contractile dysfunction to altered biomechanics in obesity
.
Gait Posture
56
,
100
-
107
.
Booth
,
F. W.
,
Chakravarthy
,
M. V.
and
Spangenburg
,
E. E.
(
2002
).
Exercise and gene expression: physiological regulation of the human genome through physical activity
.
J. Physiol. (Lond)
543
,
399
-
411
.
Bott
,
K. N.
,
Gittings
,
W.
,
Fajardo
,
V. A.
,
Baranowski
,
B. J.
,
Vandenboom
,
R.
,
LeBlanc
,
P. J.
,
Ward
,
W. E.
and
Peters
,
S. J.
(
2017
).
Musculoskeletal structure and function in response to the combined effect of an obesogenic diet and age in male C57BL/6J mice
.
Mol. Nutr. Food Res.
61
,
1700137
-
13
.
Boyle
,
K. E.
,
Patinkin
,
Z. W.
,
Shapiro
,
A. L. B.
,
Bader
,
C.
,
Vanderlinden
,
L.
,
Kechris
,
K.
,
Janssen
,
R. C.
,
Ford
,
R. J.
,
Smith
,
B. K.
,
Steinberg
,
G. R.
, et al. 
(
2017
).
Maternal obesity alters fatty acid oxidation, AMPK activity, and associated DNA methylation in mesenchymal stem cells from human infants
.
Mol. Metab.
6
,
1503
-
1516
.
Burke
,
L. M.
,
Ross
,
M. L.
,
Garvican-Lewis
,
L. A.
,
Welvaert
,
M.
,
Heikura
,
I. A.
,
Forbes
,
S. G.
,
Mirtschin
,
J. G.
,
Cato
,
L. E.
,
Strobel
,
N.
,
Sharma
,
A. P.
, et al. 
(
2017
).
Low carbohydrate, high fat diet impairs exercise economy and negates the performance benefit from intensified training in elite race walkers
.
J. Physiol. (Lond)
595
,
2785
-
2807
.
Busutil
,
R.
,
Espallardo
,
O.
,
Torres
,
A.
,
Martínez-Galdeano
,
L.
,
Zozaya
,
N.
,
Hidalgo-Vega
,
Á.
(
2017
).
The impact of obesity on health-related quality of life in Spain
.
Health Qual. Life Outcomes
15
,
460
-
411
.
Caiozzo
,
V. J.
(
2002
).
Plasticity of skeletal muscle phenotype: mechanical consequences
.
Muscle Nerve
26
,
740
-
768
.
Cannavino
,
J.
,
Brocca
,
L.
,
Sandri
,
M.
,
Grassi
,
B.
,
Bottinelli
,
R.
and
Pellegrino
,
M. A.
(
2015
).
The role of alterations in mitochondrial dynamics and PGC-1α over-expression in fast muscle atrophy following hindlimb unloading
.
J. Physiol. (Lond)
593
,
1981
-
1995
.
Cantó
,
C.
,
Gerhart-Hines
,
Z.
,
Feige
,
J. N.
,
Lagouge
,
M.
,
Noriega
,
L.
,
Milne
,
J. C.
,
Elliott
,
P. J.
,
Puigserver
,
P.
and
Auwerx
,
J.
(
2009
).
AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity
.
Nature
458
,
1056
-
1060
.
Chibalin
,
A. V.
,
Leng
,
Y.
,
Vieira
,
E.
,
Krook
,
A.
,
Björnholm
,
M.
,
Long
,
Y. C.
,
Kotova
,
O.
,
Zhong
,
Z.
,
Sakane
,
F.
,
Steiler
,
T.
, et al. 
(
2008
).
Downregulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance
.
Cell
132
,
375
-
386
.
Chin
,
E. R.
,
Olson
,
E. N.
,
Richardson
,
J. A.
,
Yang
,
Q.
,
Humphries
,
C.
,
Shelton
,
J. M.
,
Wu
,
H.
,
Zhu
,
W.
,
Bassel-Duby
,
R.
and
Williams
,
R. S.
(
1998
).
A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type
.
Genes Dev.
12
,
2499
-
2509
.
Choi
,
S.-J.
(
2016
).
Age-related functional changes and susceptibility to eccentric contraction-induced damage in skeletal muscle cell
.
Integr. Med. Res.
5
,
171
-
175
.
Choi
,
S. J.
,
Files
,
D. C.
,
Zhang
,
T.
,
Wang
,
Z.-M.
,
Messi
,
M. L.
,
Gregory
,
H.
,
Stone
,
J.
,
Lyles
,
M. F.
,
Dhar
,
S.
,
Marsh
,
A. P.
, et al. 
(
2016
).
Intramyocellular lipid and impaired myofiber contraction in normal weight and obese older adults
.
J. Gerontol. A
71
,
557
-
564
.
Ciapaite
,
J.
,
van den Berg
,
S. A.
,
Houten
,
S. M.
,
Nicolay
,
K.
,
Willems van Dijk
,
K.
and
Jeneson
,
J. A.
(
2015
).
Fiber-type-specific sensitivities and phenotypic adaptations to dietary fat overload differentially impact fast- versus slow-twitch muscle contractile function in C57BL/6J mice
.
J. Nutr. Biochem.
26
,
155
-
164
.
Cohen
,
T. J.
,
Choi
,
M.-C.
,
Kapur
,
M.
,
Lira
,
V. A.
,
Yan
,
Z.
and
Yao
,
T.-P.
(
2015
).
HDAC4 regulates muscle fiber type-specific gene expression programs
.
Mol. Cells
38
,
343
-
348
.
Craig
,
P. M.
,
Moyes
,
C. D.
and
LeMoine
,
C. M. R.
(
2017
).
Sensing and responding to energetic stress: evolution of the AMPK network
.
Comp. Biochem. Physiol. B
(
in press
).
DeNies
,
M. S.
,
Johnson
,
J.
,
Maliphol
,
A. B.
,
Bruno
,
M.
,
Kim
,
A.
,
Rizvi
,
A.
,
Rustici
,
K.
and
Medler
,
S.
(
2014
).
Diet-induced obesity alters skeletal muscle fiber types of male but not female mice
.
Physiol. Rep.
2
,
e00204
.
Deschenes
,
M. R.
(
2004
).
Effects of aging on muscle fibre type and size
.
Sports Med.
34
,
809
-
824
.
de Wilde
,
J.
,
Mohren
,
R.
,
van den Berg
,
S.
,
Boekschoten
,
M.
,
Dijk
,
K. W.-V.
,
de Groot
,
P.
,
Müller
,
M.
,
Mariman
,
E.
and
Smit
,
E.
(
2008
).
Short-term high fat-feeding results in morphological and metabolic adaptations in the skeletal muscle of C57BL/6J mice
.
Physiol. Genom.
32
,
360
-
369
.
Dickinson
,
M. H.
,
Farley
,
C.
,
Koehl
,
M.
and
Kram
,
R.
(
2000
).
How animals move: an integrative view
.
Science
288
,
100
-
106
.
Di Meo
,
S.
,
Iossa
,
S.
and
Venditti
,
P.
(
2017
).
Improvement of obesity-linked skeletal muscle insulin resistance by strength and endurance training
.
J. Endocrinol.
234
,
R159
-
R181
.
Doherty
,
T. J.
(
2003
).
Invited review: aging and sarcopenia
.
J. Appl. Physiol.
95
,
1717
-
1727
.
D'Souza
,
D. M.
,
Trajcevski
,
K. E.
,
Al-Sajee
,
D.
,
Wang
,
D. C.
,
Thomas
,
M.
,
Anderson
,
J. E.
and
Hawke
,
T. J.
(
2015
).
Diet-induced obesity impairs muscle satellite cell activation and muscle repair through alterations in hepatocyte growth factor signaling
.
Physiol. Rep.
3
,
e12506
-
e12512
.
Du
,
M.
,
Yan
,
X.
,
Tong
,
J. F.
,
Zhao
,
J.
and
Zhu
,
M. J.
(
2010
).
Maternal obesity, inflammation, and fetal skeletal muscle development
.
Biol. Reprod.
82
,
4
-
12
.
Egan
,
B.
,
Carson
,
B. P.
,
Garcia-Roves
,
P. M.
,
Chibalin
,
A. V.
,
Sarsfield
,
F. M.
,
Barron
,
N.
,
McCaffrey
,
N.
,
Moyna
,
N. M.
,
Zierath
,
J. R.
and
O'Gorman
,
D. J.
(
2010
).
Exercise intensity-dependent regulation of peroxisome proliferator-activated receptor γ coactivator-1α mRNA abundance is associated with differential activation of upstream signalling kinases in human skeletal muscle
.
J. Physiol. (Lond)
588
,
1779
-
1790
.
Eshima
,
H.
,
Tamura
,
Y.
,
Kakehi
,
S.
,
Kurebayashi
,
N.
,
Murayama
,
T.
,
Nakamura
,
K.
,
Kakigi
,
R.
,
Okada
,
T.
,
Sakurai
,
T.
,
Kawamori
,
R.
, et al. 
(
2017
).
Long-term, but not short-term high-fat diet induces fiber composition changes and impaired contractile force in mouse fast-twitch skeletal muscle
.
Physiol. Rep.
5
,
e13250
-
e13212
.
Espinosa
,
A.
,
Henríquez-Olguín
,
C.
and
Jaimovich
,
E.
(
2016
).
Reactive oxygen species and calcium signals in skeletal muscle: a crosstalk involved in both normal signaling and disease
.
Cell Calcium
60
,
172
-
179
.
Frey
,
N.
,
Richardson
,
J. A.
and
Olson
,
E. N.
(
2000
).
Calsarcins, a novel family of sarcomeric calcineurin-binding proteins
.
Proc. Natl Acad. Sci. USA
97
,
14632
-
14637
.
Frey
,
N.
,
Barrientos
,
T.
,
Shelton
,
J. M.
,
Frank
,
D.
,
Rütten
,
H.
,
Gehring
,
D.
,
Kuhn
,
C.
,
Lutz
,
M.
,
Rothermel
,
B.
,
Bassel-Duby
,
R.
, et al. 
(
2004
).
Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress
.
Nat. Med.
10
,
1336
-
1343
.
Frey
,
N.
,
Frank
,
D.
,
Lippl
,
S.
,
Kuhn
,
C.
,
Kögler
,
H.
,
Barrientos
,
T.
,
Rohr
,
C.
,
Will
,
R.
,
Müller
,
O. J.
,
Weiler
,
H.
, et al. 
(
2008
).
Calsarcin-2 deficiency increases exercise capacity in mice through calcineurin/NFAT activation
.
J. Clin. Invest.
118
,
3598
-
3608
.
Fu
,
X.
,
Zhao
,
J.-X.
,
Liang
,
J.
,
Zhu
,
M.-J.
,
Foretz
,
M.
,
Viollet
,
B.
and
Du
,
M.
(
2013
).
AMP-activated protein kinase mediates myogenin expression and myogenesis via histone deacetylase
.
Am. J. Physiol. Cell Physiol.
305
,
C887
-
C895
.
Funai
,
K.
,
Lodhi
,
I. J.
,
Spears
,
L. D.
,
Yin
,
L.
,
Song
,
H.
,
Klein
,
S.
and
Semenkovich
,
C. F.
(
2016
).
Skeletal muscle phospholipid metabolism regulates insulin sensitivity and contractile function
.
Diabetes
65
,
358
-
370
.
Funai
,
K.
,
Song
,
H.
,
Yin
,
L.
,
Lodhi
,
I. J.
,
Wei
,
X.
,
Yoshino
,
J.
,
Coleman
,
T.
and
Semenkovich
,
C. F.
(
2013
).
Muscle lipogenesis balances insulin sensitivity and strength through calcium signaling
.
J. Clin. Invest.
123
,
1229
-
1240
.
Gadducci
,
A. V.
,
de Cleva
,
R.
,
Santarém
,
G. C.
,
Silva
,
P. R.
,
Greve
,
J. M.
and
Santo
,
M. A.
(
2017
).
Muscle strength and body composition in severe obesity
.
Clinics
72
,
272
-
275
.
Garcia-Vicencio
,
S.
,
Coudeyre
,
E.
,
Kluka
,
V.
,
Cardenoux
,
C.
,
Jegu
,
A.-G.
,
Fourot
,
A.-V.
,
Ratel
,
S.
and
Martin
,
V.
(
2016
).
The bigger, the stronger? Insights from muscle architecture and nervous characteristics in obese adolescent girls
.
Int. J. Obes.
40
,
245
-
251
.
Gaur
,
V.
,
Connor
,
T.
,
Venardos
,
K.
,
Henstridge
,
D. C.
,
Martin
,
S. D.
,
Swinton
,
C.
,
Morrison
,
S.
,
Aston-Mourney
,
K.
,
Gehrig
,
S. M.
,
van Ewijk
,
R.
, et al. 
(
2017
).
Scriptaid enhances skeletal muscle insulin action and cardiac function in obese mice
.
Diabetes Obes. Metab.
19
,
936
-
943
.
Gehlert
,
S.
,
Bloch
,
W.
and
Suhr
,
F.
(
2015
).
Ca2+-dependent regulations and signaling in skeletal muscle: from electro-mechanical coupling to adaptation
.
Int. J. Mol. Sci.
16
,
1066
-
1095
.
Gordon
,
A. M.
,
Homsher
,
E.
and
Regnier
,
M.
(
2000
).
Regulation of contraction in striated muscle
.
Physiol. Rev.
80
,
853
-
924
.
Grozinger
,
C. M.
and
Schreiber
,
S. L.
(
2000
).
Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization
.
Proc. Natl Acad. Sci. USA
97
,
7835
-
7840
.
Gundersen
,
K.
(
2011
).
Excitation-transcription coupling in skeletal muscle: the molecular pathways of exercise
.
Biol. Rev.
86
,
564
-
600
.
Hales
,
C. M.
,
Carroll
,
M. D.
,
Fryar
,
C. D.
and
Ogden
,
C. L.
(
2017
).
Prevalence of obesity among adults and youth: United States, 2015–2016
.
NCHS Data Brief
288
,
1
-
8
.
Halsall
,
J. A.
and
Turner
,
B. M.
(
2016
).
Histone deacetylase inhibitors for cancer therapy: an evolutionarily ancient resistance response may explain their limited success
.
BioEssays
38
,
1102
-
1110
.
Handschin
,
C.
,
Rhee
,
J.
,
Lin
,
J.
,
Tarr
,
P. T.
and
Spiegelman
,
B. M.
(
2003
).
An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle
.
Proc. Natl. Acad. Sci. USA
100
,
7111
-
7116
.
Hardie
,
D. G.
,
Hawley
,
S. A.
and
Scott
,
J. W.
(
2006
).
AMP-activated protein kinase – development of the energy sensor concept
.
J. Physiol. (Lond)
574
,
7
-
15
.
Hardie
,
D. G.
,
Schaffer
,
B. E.
and
Brunet
,
A.
(
2016
).
AMPK: an energy-sensing pathway with multiple inputs and outputs
.
Trends Cell Biol.
26
,
190
-
201
.
Helge
,
J. W.
,
Fraser
,
A. M.
,
Kriketos
,
A. D.
,
Jenkins
,
A. B.
,
Calvert
,
G. D.
,
Ayre
,
K. J.
and
Storlien
,
L. H.
(
1999
).
Interrelationships between muscle fibre type, substrate oxidation and body fat
.
Int. J. Obes.
23
,
986
-
991
.
Hickey
,
M. S.
,
Carey
,
J. O.
,
Azevedo
,
J. L.
,
Houmard
,
J. A.
,
Pories
,
W. J.
,
Israel
,
R. G.
and
Dohm
,
G. L.
(
1995
).
Skeletal muscle fiber composition is related to adiposity and in vitro glucose transport rate in humans
.
Am. J. Physiol.
268
,
E453
-
E457
.
Hilton
,
T. N.
,
Tuttle
,
L. J.
,
Bohnert
,
K. L.
,
Mueller
,
M. J.
and
Sinacore
,
D. R.
(
2008
).
Excessive adipose tissue infiltration in skeletal muscle in individuals with obesity, diabetes mellitus, and peripheral neuropathy: association with performance and function
.
Phys. Ther.
88
,
1336
-
1344
.
Hoppeler
,
H.
(
2016
).
Molecular networks in skeletal muscle plasticity
.
J. Exp. Biol.
219
,
205
-
213
.
Houweling
,
P. J.
,
Berman
,
Y. D.
,
Turner
,
N.
,
Quinlan
,
K. G. R.
,
Seto
,
J. T.
,
Yang
,
N.
,
Lek
,
M.
,
Macarthur
,
D. G.
,
Cooney
,
G.
and
North
,
K. N.
(
2017
).
Exploring the relationship between α-actinin-3 deficiency and obesity in mice and humans
.
Int. J. Obes.
41
,
1154
-
1157
.
Hudson
,
M. B.
and
Price
,
S. R.
(
2013
).
Calcineurin: a poorly understood regulator of muscle mass
.
Int. J. Biochem. Cell Biol.
45
,
2173
-
2178
.
Hulens
,
M.
,
Vansant
,
G.
,
Lysens
,
R.
,
Claessens
,
A. L.
,
Muls
,
E.
and
Brumagne
,
S.
(
2001
).
Study of differences in peripheral muscle strength of lean versus obese women: an allometric approach
.
Int. J. Obes.
25
,
676
-
681
.
Hyatt
,
J.-P. K.
,
Nguyen
,
L.
,
Hall
,
A. E.
,
Huber
,
A. M.
,
Kocan
,
J. C.
,
Mattison
,
J. A.
,
de Cabo
,
R.
,
LaRocque
,
J. R.
and
Talmadge
,
R. J.
(
2016
).
Muscle-specific myosin heavy chain shifts in response to a long-term high fat/high sugar diet and resveratrol treatment in nonhuman primates
.
Front. Physiol.
7
,
77
.
Insenser
,
M.
,
Montes-Nieto
,
R.
,
Vilarrasa
,
N.
,
Lecube
,
A.
,
Simó
,
R.
,
Vendrell
,
J.
and
Escobar-Morreale
,
H. F.
(
2012
).
A nontargeted proteomic approach to the study of visceral and subcutaneous adipose tissue in human obesity
.
Mol. Cell Endocrinol.
363
,
10
-
19
.
Irrcher
,
I.
,
Ljubicic
,
V.
,
Kirwan
,
A. F.
and
Hood
,
D. A.
(
2008
).
AMP-activated protein kinase-regulated activation of the PGC-1α promoter in skeletal muscle cells
.
PLoS ONE
3
,
e3614
.
Iwabu
,
M.
,
Yamauchi
,
T.
,
Okada-Iwabu
,
M.
,
Sato
,
K.
,
Nakagawa
,
T.
,
Funata
,
M.
,
Yamaguchi
,
M.
,
Namiki
,
S.
,
Nakayama
,
R.
,
Tabata
,
M.
, et al. 
(
2010
).
Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1
.
Nature
464
,
1313
-
1319
.
Jäger
,
S.
,
Handschin
,
C.
,
St-Pierre
,
J.
and
Spiegelman
,
B. M.
(
2007
).
AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha
.
Proc. Natl Acad. Sci. USA
104
,
12017
-
12022
.
James
,
R. S.
(
2013
).
A review of the thermal sensitivity of the mechanics of vertebrate skeletal muscle
.
J. Comp. Physiol. B
183
,
723
-
733
.
James
,
R. S.
,
Altringham
,
J. D.
and
Goldspink
,
D. F.
(
1995
).
The mechanical-properties of fast and slow skeletal-muscles of the mouse in relation to their locomotory function
.
J. Exp. Biol.
198
,
491
-
502
.
James
,
R. S.
,
Tallis
,
J.
and
Angilletta
,
M. J.
(
2015
).
Regional thermal specialisation in a mammal: temperature affects power output of core muscle more than that of peripheral muscle in adult mice (Mus musculus)
.
J. Comp. Physiol. B
185
,
135
-
142
.
James
,
R. S.
,
Young
,
I. S.
,
Cox
,
V. M.
,
Goldspink
,
D. F.
and
Altringham
,
J. D.
(
1996
).
Isometric and isotonic muscle properties as determinants of work loop power output
.
Pflügers Archiv Eur. J. Physiol.
432
,
767
-
774
.
Jiang
,
H.
,
Li
,
H.
and
DiMario
,
J. X.
(
2006
).
Control of slow myosin heavy chain 2 gene expression by glycogen synthase kinase activity in skeletal muscle fibers
.
Cell Tissue Res.
323
,
489
-
494
.
Jiang
,
L. Q.
,
De Castro Barbosa
,
T.
,
Massart
,
J.
,
Deshmukh
,
A. S.
,
Löfgren
,
L.
,
Duque-Guimaraes
,
D. E.
,
Ozilgen
,
A.
,
Osler
,
M. E.
,
Chibalin
,
A. V.
and
Zierath
,
J. R.
(
2016
).
Diacylglycerol kinase-δ regulates AMPK signaling, lipid metabolism, and skeletal muscle energetics
.
Am. J. Physiol. Endocrin. Metab.
310
,
E51
-
E60
.
Josephson
,
R. K.
(
1993
).
Contraction dynamics and power output of skeletal muscle
.
Annu. Rev. Physiol.
55
,
527
-
546
.
Kadowaki
,
T.
,
Yamauchi
,
T.
,
Kubota
,
N.
,
Hara
,
K.
,
Ueki
,
K.
and
Tobe
,
K.
(
2006
).
Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome
.
J. Clin. Invest.
116
,
1784
-
1792
.
Kemp
,
J. G.
,
Blazev
,
R.
,
Stephenson
,
D. G.
and
Stephenson
,
G. M. M.
(
2009
).
Morphological and biochemical alterations of skeletal muscles from the genetically obese (ob/ob) mouse
.
Int. J. Obes.
33
,
831
-
841
.
Krause
,
M. P.
,
Liu
,
Y.
,
Vu
,
V.
,
Chan
,
L.
,
Xu
,
A.
,
Riddell
,
M. C.
,
Sweeney
,
G.
and
Hawke
,
T. J.
(
2008
).
Adiponectin is expressed by skeletal muscle fibers and influences muscle phenotype and function
.
Am. J. Physiol. Cell Physiol.
295
,
C203
-
C212
.
Kristensen
,
D. E.
,
Albers
,
P. H.
,
Prats
,
C.
,
Baba
,
O.
,
Birk
,
J. B.
and
Wojtaszewski
,
J. F. P.
(
2015
).
Human muscle fibre type-specific regulation of AMPK and downstream targets by exercise
.
J. Physiol. (Lond)
593
,
2053
-
2069
.
Kunstyr
,
I.
and
Leunenberger
,
H.-G. W.
(
1975
).
Gerontological data of C57BL/6J mice. I. Sex differences in survival curves
.
J. Gerontol.
30
,
157
-
162
.
Lafortuna
,
C. L.
,
Maffiuletti
,
N. A.
,
Agosti
,
F.
and
Sartorio
,
A.
(
2005
).
Gender variations of body composition, muscle strength and power output in morbid obesity
.
Int. J. Obes.
29
,
833
-
841
.
Lee
,
K. Y.
,
Singh
,
M. K.
,
Ussar
,
S.
,
Wetzel
,
P.
,
Hirshman
,
M. F.
,
Goodyear
,
L. J.
,
Kispert
,
A.
and
Kahn
,
C. R.
(
2015
).
Tbx15 controls skeletal muscle fibre-type determination and muscle metabolism
.
Nat. Commun.
6
,
8054
.
Lee-Young
,
R. S.
,
Ayala
,
J. E.
,
Fueger
,
P. T.
,
Mayes
,
W. H.
,
Kang
,
L.
and
Wasserman
,
D. H.
(
2010
).
Obesity impairs skeletal muscle AMPK signaling during exercise: role of AMPKα2 in the regulation of exercise capacity in vivo
.
Int. J. Obes.
35
,
982
-
989
.
Lin
,
J.
,
Wu
,
H.
,
Tarr
,
P. T.
,
Zhang
,
C.-Y.
,
WU
,
Z.
,
Boss
,
O.
,
Michael
,
L. F.
,
Puigserver
,
P.
,
Isotani
,
E.
,
Olson
,
E. N.
, et al. 
(
2002
).
Transcriptional co-activator PGC-1alpha drives the formation of slow-twitch muscle fibres
.
Nature
418
,
797
-
801
.
Lira
,
V. A.
,
Brown
,
D. L.
,
Lira
,
A. K.
,
Kavazis
,
A. N.
,
Soltow
,
Q. A.
,
Zeanah
,
E. H.
and
Criswell
,
D. S.
(
2010
).
Nitric oxide and AMPK cooperatively regulate PGC-1α in skeletal muscle cells
.
J. Physiol. (Lond)
588
,
3551
-
3566
.
Little
,
J. P.
,
Safdar
,
A.
,
Cermak
,
N.
,
Tarnopolsky
,
M. A.
and
Gibala
,
M. J.
(
2010
).
Acute endurance exercise increases the nuclear abundance of PGC-1α in trained human skeletal muscle
.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
298
,
R912
-
R917
.
Liu
,
Y.
,
Randall
,
W. R.
and
Schneider
,
M. F.
(
2005
).
Activity-dependent and -independent nuclear fluxes of HDAC4 mediated by different kinases in adult skeletal muscle
.
J. Cell Biol.
168
,
887
-
897
.
Ljubicic
,
V.
,
Miura
,
P.
,
Burt
,
M.
,
Boudreault
,
L.
,
Khogali
,
S.
,
Lunde
,
J. A.
,
Renaud
,
J.-M.
and
Jasmin
,
B. J.
(
2011
).
Chronic AMPK activation evokes the slow, oxidative myogenic program and triggers beneficial adaptations in mdx mouse skeletal muscle
.
Hum. Mol. Gen.
20
,
3478
-
3493
.
Lomonosova
,
Y. N.
,
Turtikova
,
O. V.
and
Shenkman
,
B. S.
(
2016
).
Reduced expression of MyHC slow isoform in rat soleus during unloading is accompanied by alterations of endogenous inhibitors of calcineurin/NFAT signaling pathway
.
J. Muscle Res. Cell Motil.
37
,
7
-
16
.
Long
,
Y. C.
,
Glund
,
S.
,
Garcia-Roves
,
P. M.
and
Zierath
,
J. R.
(
2007
).
Calcineurin regulates skeletal muscle metabolism via coordinated changes in gene expression
.
J. Biol. Chem.
282
,
1607
-
1614
.
Maffiuletti
,
N. A.
,
Jubeau
,
M.
,
Agosti
,
F.
,
De Col
,
A.
and
Sartorio
,
A.
(
2008
).
Quadriceps muscle function characteristics in severely obese and nonobese adolescents
.
Eur. J. Appl. Physiol.
103
,
481
-
484
.
Maffiuletti
,
N. A.
,
Jubeau
,
M.
,
Munzinger
,
U.
,
Bizzini
,
M.
,
Agosti
,
F.
,
De Col
,
A.
,
Lafortuna
,
C. L.
and
Sartorio
,
A.
(
2007
).
Differences in quadriceps muscle strength and fatigue between lean and obese subjects
.
Eur. J. Appl. Physiol.
101
,
51
-
59
.
Maffiuletti
,
N. A.
,
Morelli
,
A.
,
Martin
,
A.
,
Duclay
,
J.
,
Billot
,
M.
,
Jubeau
,
M.
,
Agosti
,
F.
and
Sartorio
,
A.
(
2011
).
Effect of gender and obesity on electrical current thresholds
.
Muscle Nerve
44
,
202
-
207
.
Maffiuletti
,
N. A.
,
Ratel
,
S.
,
Sartorio
,
A.
and
Martin
,
V.
(
2013
).
The impact of obesity on in vivo human skeletal muscle function
.
Curr. Obes. Rep.
2
,
251
-
260
.
Martins
,
K. J. B.
,
St-Louis
,
M.
,
Murdoch
,
G. K.
,
MacLean
,
I. M.
,
McDonald
,
P.
,
Dixon
,
W. T.
,
Putman
,
C. T.
and
Michel
,
R. N.
(
2012
).
Nitric oxide synthase inhibition prevents activity-induced calcineurin-NFATc1 signalling and fast-to-slow skeletal muscle fibre type conversions
.
J. Physiol. (Lond)
590
,
1427
-
1442
.
Matsakas
,
A.
,
Prosdocimo
,
D. A.
,
Mitchell
,
R.
,
Collins-Hooper
,
H.
,
Giallourou
,
N.
,
Swann
,
J. R.
,
Potter
,
P.
,
Epting
,
T.
,
Jain
,
M. K.
and
Patel
,
K.
(
2015
).
Investigating mechanisms underpinning the detrimental impact of a high-fat diet in the developing and adult hypermuscular myostatin null mouse
.
Skeletal Muscle
5
,
20
-
21
.
Matsunaga
,
S.
,
Inashima
,
S.
,
Yamada
,
T.
,
Watanabe
,
H.
,
Hazama
,
T.
and
Wada
,
M.
(
2003
).
Oxidation of sarcoplasmic reticulum Ca2+-ATPase induced by high-intensity exercise
.
Pflügers Archiv Eur. J. Physiol.
446
,
394
-
399
.
Mayer
,
J. M.
,
Nuzzo
,
J. L.
,
Chen
,
R.
,
Quillen
,
W. S.
,
Verna
,
J. L.
,
Miro
,
R.
and
Dagenais
,
S.
(
2012
).
The impact of obesity on back and core muscular endurance in firefighters
.
J. Obesity
2012
,
1
-
7
.
McGee
,
S. L.
and
Hargreaves
,
M.
(
2004
).
Exercise and myocyte enhancer factor 2 regulation in human skeletal muscle
.
Diabetes
53
,
1208
-
1214
.
McGee
,
S. L.
and
Hargreaves
,
M.
(
2010
).
Histone modifications and skeletal muscle metabolic gene expression
.
Clin. Exp. Pharmacol. Physiol.
37
,
392
-
396
.
McGee
,
S. L.
and
Hargreaves
,
M.
(
2011
).
Histone modifications and exercise adaptations
.
J. Appl. Physiol.
110
,
258
-
263
.
McKinsey
,
T. A.
,
Zhang
,
C.-L.
and
Olson
,
E. N.
(
2002
).
MEF2: a calcium-dependent regulator of cell division, differentiation and death
.
Trends Biochem. Sci.
27
,
40
-
47
.
Michel
,
R. N.
,
Dunn
,
S. E.
and
Chin
,
E. R.
(
2004
).
Calcineurin and skeletal muscle growth
.
Proc. Nutr. Soc.
63
,
341
-
349
.
Michel
,
R. N.
,
Chin
,
E. R.
,
Chakkalakal
,
J. V.
,
Eibl
,
J. K.
and
Jasmin
,
B. J.
(
2007
).
Ca 2+/calmodulin-based signalling in the regulation of the muscle fibre phenotype and its therapeutic potential via modulation of utrophin A and myostatin expression
.
Appl. Physiol. Nutr. Metab.
32
,
921
-
929
.
Minetto
,
M. A.
,
Botter
,
A.
,
Šprager
,
S.
,
Agosti
,
F.
,
Patrizi
,
A.
,
Lanfranco
,
F.
and
Sartorio
,
A.
(
2013
).
Feasibility study of detecting surface electromyograms in severely obese patients
.
J. Electromyogr. Kinesiol.
23
,
285
-
295
.
Mizunoya
,
W.
,
Iwamoto
,
Y.
,
Shirouchi
,
B.
,
Sato
,
M.
,
Komiya
,
Y.
,
Razin
,
F. R.
,
Tatsumi
,
R.
,
Sato
,
Y.
,
Nakamura
,
M.
and
Ikeuchi
,
Y.
(
2013
).
Dietary fat influences the expression of contractile and metabolic genes in rat skeletal muscle
.
PLoS ONE
8
,
e80152
-
e80114
.
Molkentin
,
J. D.
,
Black
,
B. L.
,
Martin
,
J. F.
and
Olson
,
E. N.
(
1995
).
Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins
.
Cell
83
,
1125
-
1136
.
Muoio
,
D. M.
and
Newgard
,
C. B.
(
2006
).
Obesity-related derangements in metabolic regulation
.
Annu. Rev. Biochem.
75
,
367
-
401
.
Myers
,
R. W.
,
Guan
,
H.-P.
,
Ehrhart
,
J.
,
Petrov
,
A.
,
Prahalada
,
S.
,
Tozzo
,
E.
,
Yang
,
X.
,
Kurtz
,
M. M.
,
Trujillo
,
M.
,
Trotter
,
D. G.
, et al. 
(
2017
).
Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy
.
Science
357
,
507
-
511
.
Narkar
,
V. A.
,
Downes
,
M.
,
Yu
,
R. T.
,
Embler
,
E.
,
Wang
,
Y.-X.
,
Banayo
,
E.
,
Mihaylova
,
M. M.
,
Nelson
,
M. C.
,
Zou
,
Y.
,
Juguilon
,
H.
, et al. 
(
2008
).
AMPK and PPARδ agonists are exercise mimetics
.
Cell
134
,
405
-
415
.
Navarro
,
A.
,
Lopez-Cepero
,
J. M.
and
Jesus Sanchez del Pino
,
M.
(
2001
).
Skeletal muscle and aging
.
Front. Biosci.
6
,
d26
-
d44
.
Nitti
,
M. D.
,
Hespe
,
G. E.
,
Kataru
,
R. P.
,
García Nores
,
G. D.
,
Savetsky
,
I. L.
,
Torrisi
,
J. S.
,
Gardenier
,
J. C.
,
Dannenberg
,
A. J.
and
Mehrara
,
B. J.
(
2016
).
Obesity-induced lymphatic dysfunction is reversible with weight loss
.
J. Physiol. (Lond)
594
,
7073
-
7087
.
Ogut
,
O.
,
Granzier
,
H.
and
Jin
,
J.-P.
(
1999
).
Acidic and basic troponin T isoforms in mature fast-twitch skeletal muscle and effect on contractility
.
Am. J. Physiol.
276
,
C1162
-
C1170
.
Paolillo
,
F. R.
,
Milan
,
J. C.
,
de Godoy Bueno
,
P.
,
Paolillo
,
A. R.
,
Borghi-Silva
,
A.
,
Parizotto
,
N. A.
,
Arena
,
R.
,
Kurachi
,
C.
and
Bagnato
,
V. S.
(
2012
).
Effects of excess body mass on strength and fatigability of quadriceps in postmenopausal women
.
Menopause
19
,
556
-
561
.
Pataky
,
Z.
,
Armand
,
S.
,
Müller-Pinget
,
S.
,
Golay
,
A.
and
Allet
,
L.
(
2013
).
Effects of obesity on functional capacity
.
Obesity
22
,
56
-
62
.
Pellegrinelli
,
V.
,
Rouault
,
C.
,
Rodríguez-Cuenca
,
S.
,
Albert
,
V.
,
Edom-Vovard
,
F.
,
Vidal-Puig
,
A.
,
Clément
,
K.
,
Butler-Browne
,
G. S.
and
Lacasa
,
D.
(
2015
).
Human adipocytes induce inflammation and atrophy in muscle cells during obesity
.
Diabetes
64
,
3121
-
3134
.
Pérez
,
L. M.
,
Pareja-Galeano
,
H.
,
Sanchis-Gomar
,
F.
,
Emanuele
,
E.
,
Lucia
,
A.
and
Gálvez
,
B. G.
(
2016
).
‘Adipaging’: ageing and obesity share biological hallmarks related to a dysfunctional adipose tissue
.
J. Physiol. (Lond)
594
,
3187
-
3207
.
Pescatello
,
L. S.
,
Kelsey
,
B. K.
,
Price
,
T. B.
,
Seip
,
R. L.
,
Angelopoulos
,
T. J.
,
Clarkson
,
P. M.
,
Gordon
,
P. M.
,
Moyna
,
N. M.
,
Visich
,
P. S.
,
Zoeller
,
R. F.
, et al. 
(
2007
).
The muscle strength and size response to upper arm, unilateral resistance training among adults who are overweight and obese
.
J. Strength Cond. Res.
21
,
307
-
313
.
Philp
,
A.
,
Chen
,
A.
,
Lan
,
D.
,
Meyer
,
G. A.
,
Murphy
,
A. N.
,
Knapp
,
A. E.
,
Olfert
,
I. M.
,
McCurdy
,
C. E.
,
Marcotte
,
G. R.
,
Hogan
,
M. C.
, et al. 
(
2011
).
Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) deacetylation following endurance exercise
.
J. Biol. Chem.
286
,
30561
-
30570
.
Potthoff
,
M. J.
,
Wu
,
H.
,
Arnold
,
M. A.
,
Shelton
,
J. M.
,
Backs
,
J.
,
McAnally
,
J.
,
Richardson
,
J. A.
,
Bassel-Duby
,
R.
and
Olson
,
E. N.
(
2007
).
Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers
.
J. Clin. Invest.
117
,
2459
-
2467
.
Prado
,
C. M. M.
,
Lieffers
,
J. R.
,
McCargar
,
L. J.
,
Reiman
,
T.
,
Sawyer
,
M. B.
,
Martin
,
L.
and
Baracos
,
V. E.
(
2008
).
Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study
.
Lancet Oncol.
9
,
629
-
635
.
Puigserver
,
P.
(
2005
).
Tissue-specific regulation of metabolic pathways through the transcriptional coactivator PGC1-α
.
Int. J. Obes.
29
,
S5
-
S9
.
Rahemi
,
H.
,
Nigam
,
N.
and
Wakeling
,
J. M.
(
2015
).
The effect of intramuscular fat on skeletal muscle mechanics: implications for the elderly and obese
.
J. R. Soc. Interface
12
,
20150365
.
Raj
,
I. S.
,
Bird
,
S. R.
and
Shield
,
A. J.
(
2010
).
Aging and the force-velocity relationship of muscles
.
Exp. Gerontol.
45
,
81
-
90
.
Rico-Sanz
,
J.
,
Rankinen
,
T.
,
Joanisse
,
D. R.
,
Leon
,
A. S.
,
Skinner
,
J. S.
,
Wilmore
,
J. H.
,
Rao
,
D. C.
and
Bouchard
,
C.
(
2003
).
Familial resemblance for muscle phenotypes in the HERITAGE family study
.
Med. Sci. Sports Ex.
35
,
1360
-
1366
.
Rolland
,
Y.
,
Lauwers-Cances
,
V.
,
Cristini
,
C.
,
van Kan
,
G. A.
,
Janssen
,
I.
,
Morley
,
J. E.
and
Vellas
,
B.
(
2009
).
Difficulties with physical function associated with obesity, sarcopenia, and sarcopenic-obesity in community-dwelling elderly women: the EPIDOS (EPIDemiologie de l'OSteoporose) Study
.
Am. J. Clin. Nutr.
89
,
1895
-
1900
.
Rolland
,
Y.
,
Lauwers-Cances
,
V.
,
Pahor
,
M.
,
Fillaux
,
J.
,
Grandjean
,
H.
and
Vellas
,
B.
(
2004
).
Muscle strength in obese elderly women: effect of recreational physical activity in a cross-sectional study
.
Am. J. Clin. Nutr.
79
,
552
-
557
.
Ross
,
F. A.
,
MacKintosh
,
C.
and
Hardie
,
D. G.
(
2016
).
AMP-activated protein kinase: a cellular energy sensor that comes in 12 flavours
.
FEBS J.
283
,
2987
-
3001
.
Roustan
,
V.
,
Jain
,
A.
,
Teige
,
M.
,
Ebersberger
,
I.
and
Weckwerth
,
W.
(
2016
).
An evolutionary perspective of AMPK-TOR signaling in the three domains of life
.
J. Exp. Bot.
67
,
3897
-
3907
.
Runhaar
,
J.
,
Koes
,
B. W.
,
Clockaerts
,
S.
and
Bierma-Zeinstra
,
S. M. A.
(
2011
).
A systematic review on changed biomechanics of lower extremities in obese individuals: a possible role in development of osteoarthritis
.
Obesity Rev.
12
,
1071
-
1082
.
Salminen
,
A.
,
Kauppinen
,
A.
and
Kaarniranta
,
K.
(
2016
).
AMPK/Snf1 signaling regulates histone acetylation: impact on gene expression and epigenetic functions
.
Cell. Sig.
28
,
887
-
895
.
Samper-Ternent
,
R.
and
Al Snih
,
S.
(
2012
).
Obesity in older adults: epidemiology and implications for disability and disease
.
Rev. Clin. Gerontol.
22
,
10
-
34
.
Sandri
,
M.
,
Lin
,
J.
,
Handschin
,
C.
,
Yang
,
W.
,
Arany
,
Z. P.
,
Lecker
,
S. H.
,
Goldberg
,
A. L.
and
Spiegelman
,
B. M.
(
2006
).
PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription
.
Proc. Natl Acad. Sci.
103
,
16260
-
16265
.
Schiaffino
,
S.
and
Reggiani
,
C.
(
2011
).
Fiber types in mammalian skeletal muscles
.
Physiol. Rev.
91
,
1447
-
1531
.
Seebacher
,
F.
,
Tallis
,
J.
,
McShea
,
K.
and
James
,
R. S.
(
2017
).
Obesity-induced decreases in muscle performance are not reversed by weight loss
.
Int. J. Obes.
41
,
1271
-
1278
.
Seto
,
J. T.
,
Quinlan
,
K. G. R.
,
Lek
,
M.
,
Zheng
,
X. F.
,
Garton
,
F.
,
MacArthur
,
D. G.
,
Hogarth
,
M. W.
,
Houweling
,
P. J.
,
Gregorevic
,
P.
,
Turner
,
N.
, et al. 
(
2013
).
ACTN3 genotype influences muscle performance through the regulation of calcineurin signaling
.
J. Clin. Invest.
123
,
4255
-
4263
.
Shen
,
T.
,
Cseresnyés
,
Z.
,
Liu
,
Y.
,
Randall
,
W. R.
and
Schneider
,
M. F.
(
2007
).
Regulation of the nuclear export of the transcription factor NFATc1 by protein kinases after slow fibre type electrical stimulation of adult mouse skeletal muscle fibres
.
J. Physiol. (Lond)
579
,
535
-
551
.
Shortreed
,
K. E.
,
Krause
,
M. P.
,
Huang
,
J. H.
,
Dhanani
,
D.
,
Moradi
,
J.
and
Ceddia
,
R. B.
(
2009
).
Muscle-specific adaptations, impaired oxidative capacity and maintenance of contractile function characterize diet-induced obese mouse skeletal muscle
.
PLoS ONE
4
,
e7293
.
Smiles
,
W. J.
and
Camera
,
D. M.
(
2015
).
More than mitochondrial biogenesis: alternative roles of PGC-1α in exercise adaptation
.
J. Physiol. (Lond)
593
,
2115
-
2117
.
Steinberg
,
G. R.
(
2018
).
Cellular energy sensing and metabolism-implications for treating diabetes
.
Diabetes
67
,
169
-
179
.
Steinberg
,
G. R.
,
Michell
,
B. J.
,
van Denderen
,
B. J. W.
,
Watt
,
M. J.
,
Carey
,
A. L.
,
Fam
,
B. C.
,
Andrikopoulos
,
S.
,
Proietto
,
J.
,
Görgün
,
C. Z.
,
Carling
,
D.
, et al. 
(
2006
).
Tumor necrosis factor α-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling
.
Cell Metab.
4
,
465
-
474
.
Stickland
,
N. C.
,
Blatt
,
R.
,
Crook
,
A. R.
and
Sutton
,
C. M.
(
1994
).
Inability of muscles in the obese mouse (ob/ob) to respond to changes in body weight and activity
.
J. Anat.
184
,
527
-
533
.
Stuart
,
C. A.
,
McCurry
,
M. P.
,
Marino
,
A.
,
South
,
M. A.
,
Howell
,
M. E. A.
,
Layne
,
A. S.
,
Ramsey
,
M. W.
and
Stone
,
M. H.
(
2013
).
Slow-twitch fiber proportion in skeletal muscle correlates with insulin responsiveness
.
J. Clin. Endocrinol. Metab.
98
,
2027
-
2036
.
Tallis
,
J.
,
Hill
,
C.
,
James
,
R. S.
,
Cox
,
V. M.
and
Seebacher
,
F.
(
2017
).
The effect of obesity on the contractile performance of isolated mouse soleus, EDL, and diaphragm muscles
.
J. Appl. Physiol.
122
,
170
-
181
.
Tanner
,
C. J.
,
Barakat
,
H. A.
,
Dohm
,
G. L.
,
Pories
,
W. J.
,
MacDonald
,
K. G.
,
Cunningham
,
P. R. G.
,
Swanson
,
M. S.
and
Houmard
,
J. A.
(
2002
).
Muscle fiber type is associated with obesity and weight loss
.
Am. J. Physiol. Endocrinol. Metab.
282
,
E1191
-
E1196
.
Teasdale
,
N.
,
Simoneau
,
M.
,
Corbeil
,
P.
,
Handrigan
,
G.
,
Tremblay
,
A.
and
Hue
,
O.
(
2013
).
Obesity alters balance and movement control
.
Curr. Obes. Rep.
2
,
235
-
240
.
Thomas
,
M. M.
,
Trajcevski
,
K. E.
,
Coleman
,
S. K.
,
Jiang
,
M.
,
Di Michele
,
J.
,
O'Neill
,
H. M.
,
Lally
,
J. S.
,
Steinberg
,
G. R.
and
Hawke
,
T. J.
(
2014
).
Early oxidative shifts in mouse skeletal muscle morphology with high-fat diet consumption do not lead to functional improvements
.
Physiol. Rep.
2
,
e12149
-
e12149
.
Tomlinson
,
D. J.
,
Erskine
,
R. M.
,
Morse
,
C. I.
,
Winwood
,
K.
and
Onambélé-Pearson
,
G. L.
(
2014
).
Combined effects of body composition and ageing on joint torque, muscle activation and co-contraction in sedentary women
.
Age
36
,
269
-
212
.
Tomlinson
,
D. J.
,
Erskine
,
R. M.
,
Morse
,
C. I.
,
Winwood
,
K.
and
Onambélé-Pearson
,
G.
(
2016
).
The impact of obesity on skeletal muscle strength and structure through adolescence to old age
.
Biogerontol.
17
,
467
-
483
.
Trajcevski
,
K. E.
,
O'Neill
,
H. M.
,
Wang
,
D. C.
,
Thomas
,
M. M.
,
Al-Sajee
,
D.
,
Steinberg
,
G. R.
,
Ceddia
,
R. B.
and
Hawke
,
T. J.
(
2013
).
Enhanced lipid oxidation and maintenance of muscle insulin sensitivity despite glucose intolerance in a diet-induced obesity mouse model
.
PLoS ONE
8
,
e71747
-
e71712
.
Turner
,
B. M.
(
2012
).
The adjustable nucleosome: an epigenetic signaling module
.
Trends Gene
28
,
436
-
444
.
Valentine
,
R. J.
,
Coughlan
,
K. A.
,
Ruderman
,
N. B.
and
Saha
,
A. K.
(
2014
).
Insulin inhibits AMPK activity and phosphorylates AMPK Ser485/491 through Akt in hepatocytes, myotubes and incubated rat skeletal muscle
.
Arch. Biochem. Biophys.
562
,
62
-
69
.
van Lunteren
,
E.
(
1996
).
Effects of genetic obesity on rat upper airway muscle and diaphragm contractile properties
.
Euro. Resp. J.
9
,
2139
-
2144
.
Vilchinskaya
,
N. A.
,
Mochalova
,
E. P.
,
Nemirovskaya
,
T. L.
,
Mirzoev
,
T. M.
,
Turtikova
,
O. V.
and
Shenkman
,
B. S.
(
2017
).
Rapid decline in MyHC I(β) mRNA expression in rat soleus during hindlimb unloading is associated with AMPK dephosphorylation
.
J. Physiol. (Lond)
595
,
7123
-
7134
.
Villareal
,
D. T.
,
Apovian
,
C. M.
,
Kushner
,
R. F.
and
Klein
,
S.
(
2005
).
Obesity in older adults: technical review and position statement of the American Society for Nutrition and NAASO, The Obesity Society
.
Obes. Res.
13
,
1849
-
1863
.
Wang
,
Y.-X.
,
Lee
,
C.-H.
,
Tiep
,
S.
,
Yu
,
R. T.
,
Ham
,
J.
,
Kang
,
H.
and
Evans
,
R. M.
(
2003
).
Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity
.
Cell
113
,
159
-
170
.
Wang
,
Z.
,
Zang
,
C.
,
Cui
,
K.
,
Schones
,
D. E.
,
Barski
,
A.
,
Peng
,
W.
and
Zhao
,
K.
(
2009
).
Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes
.
Cell
138
,
1019
-
1031
.
Warmington
,
S. A.
,
Tolan
,
R.
and
McBennett
,
S.
(
2000
).
Functional and histological characteristics of skeletal muscle and the effects of leptin in the genetically obese (ob/ob) mouse
.
Int. J. Obes.
24
,
1040
-
1050
.
Watts
,
R.
,
McAinch
,
A. J.
,
Dixon
,
J. B.
,
O'Brien
,
P. E.
and
Cameron-Smith
,
D.
(
2013
).
Increased Smad signaling and reduced MRF expression in skeletal muscle from obese subjects
.
Obesity
21
,
525
-
528
.
Wenz
,
T.
,
Rossi
,
S. G.
,
Rotundo
,
R. L.
,
Spiegelman
,
B. M.
and
Moraes
,
C. T.
(
2009
).
Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging
.
Proc. Natl Acad. Sci. USA
106
,
20405
-
20410
.
Wu
,
Z.
,
Puigserver
,
P.
,
Andersson
,
U.
,
Zhang
,
C.
,
Adelmant
,
G.
,
Mootha
,
V.
,
Troy
,
A.
,
Cinti
,
S.
,
Lowell
,
B.
and
Scarpulla
,
R. C.
(
1999
).
Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1
.
Cell
98
,
115
-
124
.
Wu
,
H.
,
Rothermel
,
B.
,
Kanatous
,
S.
,
Rosenberg
,
P.
,
Naya
,
F. J.
,
Shelton
,
J. M.
,
Hutcheson
,
K. A.
,
DiMaio
,
J. M.
,
Olson
,
E. N.
,
Bassel-Duby
,
R.
, et al. 
(
2001
).
Activation of MEF2 by muscle activity is mediated through a calcineurin-dependent pathway
.
EMBO J.
20
,
6414
-
6423
.
Wyckelsma
,
V. L.
,
Levinger
,
I.
,
McKenna
,
M. J.
,
Formosa
,
L. E.
,
Ryan
,
M. T.
,
Petersen
,
A. C.
,
Anderson
,
M. J.
and
Murphy
,
R. M.
(
2017
).
Preservation of skeletal muscle mitochondrial content in older adults: relationship between mitochondria, fibre type and high-intensity exercise training
.
J. Physiol. (Lond)
595
,
3345
-
3359
.
Yamauchi
,
T.
,
Kamon
,
J.
,
Minokoshi
,
Y.
,
Ito
,
Y.
,
Waki
,
H.
,
Uchida
,
S.
,
Yamashita
,
S.
,
Noda
,
M.
,
Kita
,
S.
,
Ueki
,
K.
, et al. 
(
2002
).
Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase
.
Nat. Med.
8
,
1288
-
1295
.
Yang
,
W.-S.
,
Lee
,
W.-J.
,
Funahashi
,
T.
,
Tanaka
,
S.
,
Matsuzawa
,
Y.
,
Chao
,
C.-L.
,
Chen
,
C.-L.
,
Tai
,
T.-Y.
and
Chuang
,
L.-M.
(
2001
).
Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin
.
J. Clin. Endocrinol. Metab.
86
,
3815
-
3819
.
Yoshida
,
Y.
,
Marcus
,
R. L.
and
Lastayo
,
P. C.
(
2012
).
Intramuscular adipose tissue and central activation in older adults
.
Muscle Nerve
46
,
813
-
816
.
Zoico
,
E.
,
Di Francesco
,
V.
,
Guralnik
,
J. M.
,
Mazzali
,
G.
,
Bortolani
,
A.
,
Guariento
,
S.
,
Sergi
,
G.
,
Bosello
,
O.
and
Zamboni
,
M.
(
2004
).
Physical disability and muscular strength in relation to obesity and different body composition indexes in a sample of healthy elderly women
.
Int. J. Obes.
28
,
234
-
241
.
Zorzano
,
A.
,
Palacín
,
M.
and
Gumà
,
A.
(
2005
).
Mechanisms regulating GLUT4 glucose transporter expression and glucose transport in skeletal muscle
.
Acta Physiol. Scand.
183
,
43
-
58
.

Competing interests

The authors declare no competing or financial interests.