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Characterizing Molecular Signaling Pathways During Hindlimb Suspension Induced Atrophy Followed by Voluntary Exercise.  A.M. Hanson¹, B.C. Harrison³, L.S. Stodieck¹, V.L. Ferguson² Dept of Aerospace Engineering¹, Mechanical Engineering², and MCD Biology³, University of Colorado, Boulder, CO.

   Prolonged exposure to the microgravity environment causes significant decreases in skeletal muscle mass and strength. Understanding the underlying mechanisms of muscle loss and recovery is imperative to the development of successful muscle atrophy countermeasures and therapies. The objectives of this study were to characterize longitudinal changes in protein expression, mRNA synthesis, and morphological adaptations in myofibers over the course of fourteen days of hindlimb suspension (HS), HS with a follow on exercise (E) period, and the effects E alone. Murf-1/Atrogin-1 and p70s6k are known regulators of muscle atrophy, located downstream of the IGF1 signaling pathway. Increased expression of Murf-1/Atrogin-1 is indicative of a catabolism, whereas activation of p70s6k indicates protein synthesis and muscle hypertrophy. Young adult C57BL/6 male mice (27.5±1 grams) were evenly divided (n=7) into four treatment groups: Control, 14-days HS, seven days of exercise (voluntary wheel running) (E7), and 14-days HS followed by seven days of exercise (HSE7). Compared to controls, expression of p70s6k decreased 17.3% in HS mice, increased 11.8% in E7 mice, and returned to control values in the HSE7 mice. Levels of Murf-1/Atrogin-1 expression peaked at a 40-fold increase compared to controls after 1-day of suspension, and dropped to a 4-fold increase at day fourteen. Murf-1/Atrogin-1 expression dropped to a 2-fold increase over controls with in the HSE7 mice; exercise alone did not affect expression Murf-1/Atrogin-1.  IGF1 expression increased slightly through seven days of suspension, but returned to control values at the end of the suspension period. Expression of type-I fibers in the soleus decreased in number and size in the HS mice, increased in area in the E7 group, and returned to control values in size, but not numbers with exercise following suspension. These results show a clear correlation between p70s6k and Mruf-1/Atrogin-1 expression and morphological changes in muscle undergoing unloading induced atrophy. (Supported by NASA: NC C8-242)