Abstract
The purpose of our study was to compare two acquired muscle atrophies and the use of myostatin inhibition for their treatment. Myostatin naturally inhibits skeletal muscle growth by binding to ActRIIB, a receptor on the cell surface of myofibers. Because blocking myostatin in an adult wild-type mouse induces profound muscle hypertrophy, we applied a soluble ActRIIB receptor to models of disuse (limb immobilization) and denervation (sciatic nerve resection) atrophy. We found that treatment of immobilized mice with ActRIIB prevented the loss of muscle mass observed in placebo-treated mice. Our results suggest that this protection from disuse atrophy is regulated by serum and glucocorticoid-induced kinase (SGK) rather than by Akt. Denervation atrophy, however, was not protected by ActRIIB treatment, yet resulted in an upregulation of the pro-growth factors Akt, SGK and components of the mTOR pathway. We then treated the denervated mice with the mTOR inhibitor rapamycin and found that, despite a reduction in mTOR activation, there is no alteration of the atrophy phenotype. Additionally, rapamycin prevented the denervation-induced upregulation of the mTORC2 substrates Akt and SGK. Thus, our studies show that denervation atrophy is not only independent from Akt, SGK and mTOR activation but also has a different underlying pathophysiological mechanism than disuse atrophy.
Highlights
Healthy skeletal muscle maintains a balance between protein synthesis and protein degradation (Glass, 2010; McKinnell and Rudnicki, 2004)
The authors investigate the possible benefits of myostatin inhibition in two mouse models of acquired muscle atrophy: a hindlimb immobilization model and a sciatic nerve resection model
The authors demonstrate that myostatin inhibition can protect mice from developing disuse atrophy but that myostatin inhibition has no effect on an atrophy resulting from the loss of the neuromuscular connection
Summary
Healthy skeletal muscle maintains a balance between protein synthesis and protein degradation (Glass, 2010; McKinnell and Rudnicki, 2004). Received 31 August 2013; Accepted 3 February 2014 that is disrupted in all forms of skeletal muscle atrophy regardless of their etiology (Lecker and Goldberg, 2002; Lecker et al, 2004; Sacheck et al, 2007). This paradigm is thought to revolve mainly around the insulin-like growth factor (IGF) pathway and the serinethreonine kinase protein kinase B, commonly referred to as Akt (Glass, 2010; Rommel et al, 2001; Schiaffino and Mammucari, 2011). The Akt signaling cascade can regulate muscle mass by both inhibiting protein degradation and promoting protein synthesis; overexpression of Akt can lead to both muscle hypertrophy and the prevention of atrophy (Bodine et al, 2001b; Glass, 2010; Rommel et al, 2001)
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