Inhibitors of Myostatin- and Proteasome-Dependent Signaling for Attenuating Muscle Wasting

Myostatin is a major negative regulator of muscle mass. Interestingly, myostatin can modulate the expression and functional activity of myogenic regulatory factors such as MyoD and Forkhead BoxO (FOXO). Recently, Akt, a crucial enhancer of muscle hypertrophy, has been shown to interact with Smad2 and 3, downstream of a myostatin-dependent pathway. Ubiquitin-proteasome signaling is the most common system of protein degradation during rapid musclular atrophy after denervation, immobilization, or hindlimb suspension (unweighting) through the downstream mediator Atrogin-1 and FOXO. Deregulation of myostatin signaling has been implicated in the pathology of a number of major muscle wasting disorders including several muscular dystrophy, sarcopenia, cachexia, and amyotrophic lateral sclerosis. Worldwide, the pharmaceutical industry is actively developing better strategies for targeting muscle wasting, in particular, myostatin and proteasome-inhibitors. This patent review provides an overview of recent attempts to attenuate or inhibit muscle wasting using new and improved myostatin- and proteasome-linked agents. Proteasome inhibitor may not be appropriate for blocking muscle atrophy induced by sarcopenia and cachexia.