Translating Mighty Mice into Neuromuscular Therapeutics: Is Bigger Muscle Better?

Abstract

There is increasing clinical research interest in skeletal muscle due in part to the rising incidence of morbidities associated with muscle, particularly insulin resistance and type 2 diabetes (inactive and over-fed muscle) as well as aging and frailty (sarcopenia). A promising avenue of drug development is focused on muscle hypertrophy: the rationale being that a larger muscle is healthier and stronger. Molecular targets for drug development include the myostatin pathway and the IGF1/AKT1 pathway, with both preclinical and clinical testing underway in the inherited muscular dystrophies and in other muscle disorders. As research intensifies, the complexity of these networks in both normal physiology and pathophysiology is becoming evident. As described by Parsons et al1 in this issue of The American Journal of Pathology, myostatin blockade in mouse models of inherited muscle disease is highly variable in its effectiveness, depending on the disease model used, the specific muscle groups studied, and even the age of the animal. Here, we discuss the underlying rationale and current data concerning modulation of muscle size in clinical disorders of muscle.