Denervation atrophy is indepedent from AKT and mTOR activation and responds differently than disuse atrophy to myostatin inhibition

Myostatin is a TGF-β signaling family member that acts as a natural inhibitor of skeletal muscle growth via binding to the ActRIIB receptor on the cell surface of myofibers. Because myostatin inhibition in a wild type adult mouse induces profound muscle hypertrophy several pharmaceutical companies are currently testing their efficacy to treat inherited muscle disorders. In my study, I investigated the application of a soluble ActRIIB receptor for prevention of systemic steroid induced myopathy and the single limb atrophies due to disuse and denervation. Based on muscle mass and fiber diameter measurements I found that disuse atrophy and steroid myopathy, but not denervation atrophy, was prevented by treatment with ActRIIB. I then focused my analysis on the comparison of disuse and denervation atrophy in order to find a molecular basis for the differences in phenotypic outcome. My results show that ActRIIB is able to downregulate non-canonical TGF-13 signaling markers in disuse, but not denervation, atrophy. Treatment of denervated muscle with two other types of TGF-f3 inhibitors also did not rescue the phenotype nor did they reduce TGF-r3 signaling. Denervation also leads to a loss in activation of the JAK/STAT pathway, but treatment of denervated muscle with a JAK/STAT activator does not rescue the phenotype. My results also suggest that disuse atrophy, and protection from atrophy, is regulated by SGK instead of Akt. In denervation atrophy however, Akt, SGK, and many components of the mTOR pathway, are all significantly upregulated compared to controls. In order to determine if the upregulation in mTOR signaling was detrimental or a compensatory mechanism, I then treated the denervated mice with the mTOR inhibitor rapamycin. Rapamycin did not change the denervation atrophy phenotype even though there was reduced activation of the mTORC I and mTORC2 complexes compared to placebo treated mice. In addition, rapamycin treatment prevented the denervation-induced upregulation of the mTORC2 complex substrates Akt and SGK. Thus, my studies are consistent with a model in which denervation atrophy is not only independent from Akt, SGK, and mTOR activation but also has a different underlying pathophysiological mechanism than disuse atrophy.