Skeletal muscle comprises the largest organ system within our bodies, and over time, skeletal muscle has evolved in response to the earth's gravitational forces. By reducing the gravitational…

Skeletal muscle comprises the largest organ system within our bodies, and over time, skeletal muscle has evolved in response to the earth's gravitational forces. By reducing the gravitational loading that our muscles are accustomed to, such as occurs during exposure to the microgravity environment of spaceflight, atrophy and weakening of the postural, antigravity muscles will occur (1, 2). These changes are allowed to take place because of the constant state of turnover that characterizes skeletal muscle, which permits muscle to respond to changes in external loading by increasing, decreasing, or maintaining muscle mass. Spaceflight, as well as the ground-based analogs, i.e., bed-rest and rodent hindlimb unloading, lead to a loss of weight in antigravity muscles such as the soleus that is noticeable within two days and is the result of an imbalance in muscle protein-turnover (3, 4, 5, 6). This imbalanced muscle protein-turnover is described as a reduction in muscle protein synthesis and an upregulation of muscle protein degradation. During skeletal muscle disuse, a regulator of protein-turnover is the activation of the ubiquitin proteasome pathway, which is the primary mode of muscle protein degradation (7). The ubiquitin proteasome pathway targets the myofibril proteins that make up the myofibril fraction, such as myosin heavy chain (MHC), actin, and tropomyosin, all of which are integral components of the contracti LE apparatus and involved in force development and muscle contraction (6, 7). Lessening the external load placed on the muscle, as with microgravity exposure or hindlimb unloading, will also alter the composition of muscle fibers, leading to a transition from the slow, antigravity phenotype to a faster isoform muscle fiber (8, 9). Together, these changes lead to a reduction in function characterized by decreased force output, power output, and decreased stamina. Reduced muscle function can be detrimental to astronauts during spaceflight and also upon return from the microgravity environment to the 19 environment of earth.