Studies of physiological systems under extreme conditions teach us important lessons regarding the basics of life. One fascinating extreme condition is space travel. Space travel affects physiological functions in many ways, and one of its key signatures is muscle atrophy. Muscle atrophy occurs when there is an imbalance in the rate of protein synthesis and degradation. However, the molecular mechanisms that lead to muscle wasting under microgravity remain a mystery. Given the difficulty of carrying out experiments in space, experimental protocols have been developed to study the effects of weightlessness on the ground. One common protocol to induce muscle atrophy suspends rats by the tail to prevent the animals from bearing weight on their hindlimbs. Denervation of muscles is another method for causing muscle atrophy. In order to determine if these two protocols are good surrogates for space travel and to characterize the effects of microgravity at the molecular level, Takeshi Nikawa and collaborators used a DNA microarray to examine the expression of 26 000 genes in the muscle of 8-day-old rats exposed to tail suspension, denervation and space travel for 16 days in the space shuttle Columbia.

All three treatments led to significant muscle atrophy, with tail suspension causing the most dramatic loss in muscle mass, namely an 86%reduction compared with controls. For the three protocols, muscle atrophy was accompanied by profound changes in cellular gene expression patterns. Indeed,the expression of genes involved in cellular functions ranging from metabolism to cell structure was affected. However, the cellular gene expression pattern of the muscle from space-flown rats was unique. Space travel resulted in a distinct change in the expression of mitochondrial and cytoskeletal genes as well as in the expression of genes related to protein degradation. Therefore,the two protocols used on the ground to mimic microgravity hint at the existence of different signalling pathways leading to muscle atrophy and,also, they do not reproduce the molecular changes observed in space. The authors observed that the unique decrease in the expression of cytoskeletal genes in the muscle of space-flown rats was accompanied by an aberrant distribution of mitochondria. Furthermore, space travel resulted in the upregulation of oxidative stress genes.

The authors propose a new model to explain muscle atrophy during space travel, where mitochondria function as gravity sensors. Microgravity would decrease the expression of cytoskeletal proteins resulting in disturbances in the distribution of mitochondria within the cells. Finding themselves in unexpected territories, the mitochondria would spill reactive oxygen species,which cause oxidative stress, and produce inappropriate amounts of ATP resulting in muscle atrophy. Overall, this paper lays the foundation to test the mitochondrial theory of muscle atrophy.

Nikawa, T., Ishidoh, K., Hirasaka, K., Ishihara, I., Ikemoto,M., Kano, M., Kominami, E., Nonaka, I., Ogawa, T., Adams, G. R. et al.(
). Skeletal muscle gene expression in space-flown rats.