A myosin-lacZ fusion, expressed in 103 muscle cells of Caenorhabditis elegans, reports on how proteolysis in muscle is controlled by neural and intramuscular signals. Upon acute starvation, the fusion protein is degraded in the posterior 63 cells of the body-wall muscle, but remains stable in 32 anterior body-wall muscles and 8 vulval muscle cells. This distinction correlates with differences in the innervation of these cells. Reporter protein in the head and vulval muscles becomes labile upon genetic ‘denervation’ in mutants that have blocks in pre-synaptic synthesis or release of acetylcholine (ACh) or post-synaptic reception at nicotinic ACh receptors (nAChR), whereas protein in all 103 muscles is stabilized by the nicotinic agonist levamisole in the absence of ACh production. Levamisole does not stabilize muscle protein in nAChR mutants that are behaviorally resistant to levamisole. Neural inputs thus exert negative control over the proteolytic process in muscle by stimulating muscle nicotinic ACh receptors.

REFERENCES

Alfonso
A.
,
Grundahl
K.
,
Duerr
J. S.
,
Han
H. P.
,
Rand
J. B.
(
1993
).
The Caenorhabditis elegans unc-17 gene: a putative vesicular acetylcholine transporter.
Science
261
,
617
619
Alfonso
A.
,
Grundahl
K.
,
McManus
J. R.
,
Rand
J. B.
(
1994
).
Cloning and characterization of the choline acetyltransferase structural gene (cha-1) from C. elegans.
J. Neurosci
14
,
2290
2300
Argiles
J. M.
,
Lopez Soriano
F. J.
) (
1996
).
The ubiquitin-dependent proteolytic pathway in skeletal muscle: its role in pathological states.
Trends Pharmacol. Sci
17
,
223
226
Attaix
D.
,
Taillandier
D.
,
Combaret
L.
,
Ralliere
C.
,
Larbaud
D.
,
Aurousseau
E.
,
Tanaka
K.
(
1997
).
Expression of subunits of the 19S complex and of the PA28 activator in rat skeletal muscle.
Mol. Biol. Rep
24
,
95
98
Attaix
D.
,
Aurousseau
E.
,
Combaret
L.
,
Kee
A.
,
Larbaud
D.
,
Ralliere
C.
,
Souweine
B.
,
Taillandier
D.
,
Tilignac
T.
(
1998
).
Ubiquitin-proteasome-dependent proteolysis in skeletal muscle.
Reprod. Nutr. Dev
38
,
153
165
Auclair
D.
,
Garrel
D. R.
,
Chaouki Zerouala
A.
,
Ferland
L. H.
(
1997
).
Activation of the ubiquitin pathway in rat skeletal muscle by catabolic doses of glucocorticoids.
Am. J. Physiol
272
,
1007
1016
Ballivet
M.
,
Alliod
C.
,
Bertrand
S.
,
Bertrand
D.
(
1996
).
Nicotinic acetylcholine receptors in the nematode Caenorhabditis elegans.
J. Mol. Biol
258
,
261
269
Baumeister
W.
,
Cejka
Z.
,
Kania
M.
,
Seemueller
E.
(
1997
).
The proteasome: A macromolecular assembly designed to confine proteolysis to a nanocompartment.
Biol. Chem
378
,
121
130
Biolo
G.
,
Toigo
G.
,
Ciocchi
B.
,
Situlin
R.
,
Iscra
F.
,
Gullo
A.
,
Guarnieri
G.
(
1997
).
Metabolic response to injury and sepsis: changes in protein metabolism.
Nutrition
13
,
52
–.
Bolten
S. L.
,
Powell Abel
P.
,
Fischhoff
D. A.
,
Waterston
R. H.
(
1984
).
The sup-7(st5) X gene of Caenorhabditis elegans encodes a tRNATrp UAGamber suppressor.
Proc. Nat. Acad. Sci. USA
81
,
6784
6788
Brenner
S.
(
1974
).
The genetics of Caenorhabditis elegans.
Genetics
77
,
71
94
Consortium, The C. elegans Sequencing
(
1998
).
Genome sequence of the nematode C. elegans: a platform for investigating biology.
Science
282
,
2012
2018
Cooney
R. N.
,
Kimball
S. R.
,
Vary
T. C.
(
1997
).
Regulation of skeletal muscle protein turnover during sepsis: mechanisms and mediators.
Shock
7
,
1
16
Coux
O.
,
Tanaka
K.
,
Goldberg
A.
(
1996
).
Structure and functions of the 20S and 26S proteasomes.
Annu. Rev. Biochem
65
,
801
847
Craiu
A.
,
Gaczynska
M.
,
Akopian
T.
,
Gramm
C. F.
,
Fenteany
G.
,
Goldberg
A. L.
,
Rock
K. L.
(
1997
).
Lactacystin and clasto-lactacystin beta-lactone modify multiple proteasome beta-subunits and inhibit intracellular protein degradation and major histocompatibility complex class I antigen presentation.
J. Biol. Chem
272
,
13437
13445
Epstein
H. F.
,
Waterston
R. H.
,
Brenner
S.
(
1974
).
A mutant affecting the heavy chain of myosin in Caenorhabditis elegans.
J. Mol. Biol
90
,
291
300
Farley
J. R.
,
Puzas
J. E.
,
Baylink
D. J.
(
1982
).
Effect of skeletal alkaline phosphatase inhibitors on bone cell proliferation in vitro.
Miner. Electrolyte Metab
7
,
316
323
Fire
A.
,
Waterston
R. H.
(
1989
).
Proper expression of myosin genes in transgenic nematodes.
EMBO J
8
,
3419
3428
Fire
A.
(
1992
).
Histochemical technqiues for locating Escherichia col i-galactosidase activity in transgenic organisms.
Gene Anal. Tech. Appl
9
,
151
158
Fleming
J. T.
,
Squire
M. D.
,
Barnes
T. M.
,
Tornoe
C.
,
Matsuda
K.
,
Ahnn
J.
,
Fire
A.
,
Sulston
J. E.
,
Barnard
E. A.
,
Sattelle
D. B.
, et al. 
(
1997
).
Caenorhabditis elegans levamisole resistance genes lev-1, unc-29, and unc-38 encode functional nicotinic acetylcholine receptor subunits.
J. Neurosci
17
,
5843
5857
Furuno
K.
,
Goodman
M. N.
,
Goldberg
A. L.
(
1990
).
Role of different proteolytic systems in the degradation of muscle proteins during denervation atrophy.
J. Biol. Chem
265
,
8550
8557
Garcia Martinez
C.
,
Llovera
M.
,
Agell
N.
,
Lopez Soriano
F. J.
,
Argiles
J. M.
(
1995
).
Ubiquitin gene expression in skeletal muscle is increased during sepsis: Involvement of TNF-alpha but not IL-1.
Biochem. Biophys. Res. Commun
217
,
839
844
Gropper
R.
,
Brandt
R. A.
,
Elias
S.
,
Bearer
C. F.
,
Mayer
A.
,
Schwartz
A. L.
,
Ciechanover
A.
(
1991
).
The ubiquitin-activating enzyme, E1, is required for stress-induced lysosomal degradation of cellular proteins.
J. Biol. Chem
266
,
3602
3610
Hasselgren
P. O.
,
Fischer
J. E.
(
1997
).
The ubiquitin-proteasome pathway: review of a novel intracellular mechanism of muscle protein breakdown during sepsis and other catabolic conditions.
Ann. Surg
225
,
307
316
Hershko
A.
,
Ciechanover
A.
(
1998
).
The ubiquitin system.
Annu. Rev. Biochem
67
,
425
479
Hobler
S.
,
Tiao
G.
,
Fischer
J. E.
,
Hasselgren
P. O.
(
1998
).
The sepsis-induced increase in muscle proteolysis is associated with increased 20S proteasome activity and is blocked by 20S proteasome inhibitors.
Surgical Forum
47
,
14
17
Hobler
S. C.
,
Tiao
G.
,
Fischer
J. E.
,
Monaco
J.
,
Hasselgren
P. O.
(
1998
).
Sepsis-induced increase in muscle proteolysis is blocked by specific proteasome inhibitors.
Am. J. Physiol
274
,
30
37
Hobler
S. C.
,
Wang
J. J.
,
Williams
A. B.
,
Melandri
F.
,
Sun
X.
,
Fischer
J. E.
,
Hasselgren
P. O.
(
1999
).
Sepsis is associated with increased ubiquitin conjugating enzyme E214k mRNA in skeletal muscle.
Am. J. Physiol
276
,
468
473
Hosono
R.
,
Sassa
T.
,
Kuno
S.
(
1989
).
Spontaneous mutations of trichlorfon resistance in the nematode, Caenorhabditis elegans.
Zool. Sci
6
,
697
708
Jin
Y.
,
Jorgensen
E.
,
Hartwieg
E.
,
Horvitz
H. R.
(
1999
).
The Caenorhabditis elegans gene unc-25 encodes glutamic acid decarboxylase and is required for synaptic transmission but not synaptic development.
J. Neurosci
19
,
539
548
Lee
D. H.
,
Goldberg
A. L.
(
1996
).
Selective inhibitors of the proteasome-dependent and vacuolar pathways of protein degradation in Saccharomyces cerevisiae.
J. Biol. Chem
271
,
27280
27284
Lewis
J. A.
,
Wu
C.-H.
,
Berg
H.
,
Levine
J. H.
(
1980
).
The genetics of levamisole resistance in the nematode Caenorhabditis elegans.
Genetics
95
,
905
928
Lewis
J. A.
,
Wu
C.-H.
,
Levine
J. H.
,
Berg
H.
(
1980
).
Levamisole-resistant mutants of the nematode Caenorhabditis elegans appear to lack pharmacological acetylcholine receptors.
Neuroscience
5
,
967
989
Li
J. B.
,
Goldberg
A. L.
(
1976
).
Effects of food deprivation on protein synthesis and degradation in rat skeletal muscles.
Am. J. Physiol
231
,
441
448
Mackenzie
J. M.
Jr.
,
Epstein
H. F.
(
1980
).
Paramyosin is neccessary for determination of nematode thick filament in vivo.
Cell
22
,
747
755
Maruyama
I. N.
,
Brenner
S.
(
1991
).
A phorbol ester/diacylglycerol-binding protein encoded by the unc-13 gene of Caenorhabditis elegans.
Proc. Nat. Acad. Sci. USA
88
,
5729
5733
McIntire
S. L.
,
Jorgensen
E.
,
Kaplan
J.
,
Horvitz
H. R.
(
1993
).
TheGABAergic nervous system of Caenorhabditis elegans.
Nature
364
,
337
341
McIntire
S. L.
,
Reimer
R. J.
,
Schuske
K.
,
Edwards
R. H.
,
Jorgensen
E. M.
(
1997
).
Identification and characterization of the vesicular GABA transporter.
Nature
389
,
870
876
Medina
R.
,
Wing
S. W.
,
Haas
A.
,
Goldberg
A. L.
(
1991
).
Activation of the ubiquitin-ATP-dependent proteolytic system in skeletal muscle during fasting and denervation atrophy.
Biomed. Biochim. Acta
50
,
347
356
Mitch
W. E.
,
Goldberg
A. L.
(
1996
).
Mechanisms of muscle wasting: The role of the ubiquitin-proteasome pathway.
New Engl. J. Med
335
,
1897
1905
Mitch
W. E.
(
1998
).
Robert H Herman Memorial Award in Clinical Nutrition Lecture, 1997. Mechanisms causing loss of lean body mass in kidney disease.
Am. J. Clin. Nutr
67
,
359
366
Okkema
P. G.
,
Harrison
S. W.
,
Plunger
V.
,
Aryana
A.
,
Fire
A.
(
1993
).
Sequence requirements for myosin gene expression and regulation in Caenorhabditis elegans.
Genetics
135
,
385
404
Rand
J. B.
(
1989
).
Genetic analysis of the cha-1—unc-17 gene complex in Caenorhabditis.
Genetics
122
,
73
80
Rooyackers
O. E.
,
Nair
K. S.
(
1997
).
Hormonal regulation of human muscle protein metabolism.
Annu. Rev. Nutr
17
,
457
485
Rosenbluth
J.
(
1965
).
Structural organization of obliquely striated muscle fibers in Ascaris lumbricoides.
J. Cell Biol
25
,
495
515
Sassa
T.
,
Harada
S.
,
Ogawa
H.
,
Rand
J. B.
,
Maruyama
I. N.
,
Hosono
R.
(
1999
).
Regulation of the UNC-18-Caenorhabditis elegans syntaxin complex by UNC-13.
J. Neurosci
19
,
4772
4777
Sebastiano
M.
,
D'Alessio
M.
,
Bazzicalupo
P.
(
1986
).
Beta-glucuronidase mutants of the nematode Caenorhabditis elegans.
Genetics
112
,
459
468
Solomon
V.
,
Goldberg
A. L.
(
1996
).
Importance of the ATP-ubiquitin-proteasome pathway in the degradation of soluble and myofibrillar proteins in rabbit muscle extracts.
J. Biol. Chem
271
,
26690
26697
Squire
M. D.
,
Tornoe
C.
,
Baylis
H. A.
,
Fleming
J. T.
,
Barnard
E. A.
,
Sattelle
D. B.
(
1995
).
Molecular cloning and functional co-expression of a Caenorhabditis elegans nicotinic acetylcholine receptor subunit (acr-2).
Receptors Channels
3
,
107
115
Stone
S.
,
Shaw
J. E.
(
1993
).
A Caenorhabditis elegans act-4::lacZ fusion: use as a transformation marker and analysis of tissue-specific expression.
Gene
131
,
167
173
Sulston
J. E.
,
Horvitz
H. R.
(
1977
).
Post-embryonic cell lineages of the nematode, Caenorhabditis elegans.
Dev. Biol
56
,
110
156
Taillandier
D.
,
Aurousseau
E.
,
Meynial Denis
D.
,
Bechet
D.
,
Ferrara
M.
,
Cottin
P.
,
Ducastaing
A.
,
Bigard
X.
,
Guezennec
C. Y.
,
Schmid
H. P.
, et al. 
(
1996
).
Coordinate activation of lysosomal, Ca2+-activated and ATP-ubiquitin-dependent proteinases in the unweighted rat soleus muscle.
Biochem. J
316
,
65
72
Tawa
N. E.
Jr.
,
Odessey
R.
,
Goldberg
A. L.
(
1997
).
Inhibitors of the proteasome reduce the accelerated proteolysis in atrophying rat skeletal muscles.
J. Clin. Invest
100
,
197
203
Tiao
G.
,
Hobler
S.
,
Wang
J. J.
,
Meyer
T. A.
,
Luchette
F. A.
,
Fisher
J. E.
,
Hasselgren
P. O.
(
1997
).
Sepsis is associated with increased mRNAs of the ubiquitin-proteasome proteolytic pathway in human skeletal muscle.
J. Clin. Invest
99
,
163
168
Toomey
D.
,
Redmond
H. P.
,
Bouchier Hayes
D.
(
1995
).
Mechanisms mediating cancer cachexia.
Cancer
76
,
2418
2426
Varshavsky
A.
(
1997
).
The ubiquitin system.
Trends Biochem. Sci
22
,
383
387
Waterston
R. H.
,
Epstein
H. F.
,
Brenner
S.
(
1974
).
Paramyosin of Caenorhabditis elegans.
J. Mol. Biol
90
,
285
290
White
J. G.
,
Southgate
E.
,
Thomson
J. N.
,
Brenner
S.
(
1986
).
The structure of the nervous system of Caenorhabditis elegans.
Phil. Trans. Roy. Soc. Ser. B
314
,
1
340
Wing
S. S.
,
Banville
D.
(
1994
).
14-kDa ubiquitin-conjugating enzyme: structure of the rat gene and regulation upon fasting and by insulin.
Am. J. Physiol
267
,
39
–.
Zdinak
L. A.
,
Greenberg
I. B.
,
Szewczyk
N. J.
,
Barmada
S. J.
,
Cardamone Rayner
M.
,
Hartman
J. J.
,
Jacobson
L. A.
(
1997
).
Transgene-coded chimeric proteins as reporters of intracellular proteolysis: starvation-induced catabolism of a lacZ fusion protein in muscle cells of Caenorhabditis elegans.
J. Cell Biochem
67
,
143
153
This content is only available via PDF.