Humans are an integral part of the engineered systems that will enable return to the Moon and eventually travel to Mars. Major advancements in countermeasure development addressing deleterious effects of microgravity and reduced gravity on the musculoskeletal system need to be made to ensure mission safety and success.

The primary objectives of this dissertation are to advance the knowledge and understanding of skeletal muscle atrophy, and support development of novel countermeasures for disuse atrophy to enable healthy long-duration human spaceflight. Models simulating microgravity and actual spaceflight were used to examine the musculoskeletal adaptations during periods of unloading. Myostatin inhibition, a novel anti-atrophy drug therapy, and exercise were examined as a means of preventing and recovering from disuse atrophy. A combination of assays was used to quantify adaptation responses to unloading and examine efficacy of the countermeasures. Body and muscle masses were collected to analyze systemic changes due to treatments. Hindlimb strength and individual muscle forces were measured to demonstrate functional adaptations to treatments. Muscle fiber morphology and myosin heavy chain (MHC) expression was examined to identify adaptations at the cellular level. Protein synthesis signals insulin-like growth factor-1 (IGF-1), Akt, and p70s6 kinase;​ and the degradation signals Atrogin-1 and MuRF-1 were examined to identify adaptations at the molecular level that ultimately lead to muscle hypertrophy and atrophy.

A time course study provided a thorough characterization of the adaptation of skeletal muscle during unloading in C57BL/6 mice, and baseline data for comparison to and evaluation of subsequent studies. Time points defining the on-set and endpoints of disuse muscle atrophy were identified to enable characterization of rapid vs. long-term responses of skeletal muscle to hindlimb suspension. Unloading-induced atrophy primarily resulted from increased protein degradation at early time points that predominantly affected slow-twitch muscle fibers. A second study examined the use of exercise as a means of recovery from disuse atrophy. Contrary to previous reports, a short duration of exercise following disuse provided a functional benefit to contractile mechanisms and increased resistance to fatigue – possibly due to increased expression of fast-twitch fibers. Two additional studies examined the efficacy of a myostatin inhibitor in combination with hindlimb unloading and in spaceflight. Myostatin inhibition increased expression of markers within the muscle synthesis pathway in both models. The myostatin inhibitors were potent enough for the skeletal muscles to overcome the atrophying effects of musculoskeletal unloading as demonstrated by increased mass and strength. Myostatin inhibition is demonstrated to be a very promising and effective treatment for disuse muscle atrophy that may benefit astronauts and patients with muscle wasting diseases. This dissertation provides the first analyses of an unloading model in combination with a myostatin inhibitor as a countermeasure for skeletal muscle disuse atrophy while exploring the specific roles of muscle function, morphology, and translational signaling pathways.