T.O.6 Myostatin inhibitor ActIIb rescues atrophy and protects muscle growth signaling pathways in immobilization but not denervation

Abstract Myostatin, a member of the TGFβ signaling family, acts as a natural inhibitor of skeletal muscle growth via binding to the ActIIb receptor on the cell surface of myofibers. Because myostatin inhibition in a normal mouse induces profound muscle hypertrophy, we investigated the use of a soluble ActIIb receptor as a treatment for immobilization and denervation atrophy in mice. We found that immobilized mice were protected from atrophy after three weeks of administration of ActIIb as compared to the placebo treated group. In contrast, ActIIb treatment did not rescue muscle atrophy in denervated mice. Molecular analysis of the skeletal muscle from immobilized mice demonstrated that ActIIb treatment leads to the protection of several pro-growth pathways. We found that mice treated with ActIIb maintained mTOR signaling while the placebo immobilized group showed a significant decrease in many components of this pathway. The ActIIb treated group was also protected from the loss of anti-apoptotic and pro-growth Jak/Stat signaling markers as compared to placebo immobilized mice. In contrast, and in agreement with the muscle phenotype, molecular analysis of the denervated mice showed a loss of anti-apoptotic and an increase in pro-autophagic markers suggesting that these pathways mediate the loss of muscle mass. In addition, denervated mice demonstrated a pronounced disregulation of pro-growth markers in the Jak/Stat signaling cascade. Surprisingly, denervated mice revealed upregulation of many components of mTOR signaling cascade. As this pathway is associated with hypertrophy, we suggest that this is a compensatory mechanism to prevent further atrophy. These results highlight that myostatin inhibition is a valid therapeutic option for conditions associated with disuse atrophy, but not for denervation induced atrophy. Furthermore, our results indicate that different molecular mechanisms drive loss of muscle mass in immobilization and denervation atrophy.