Grant: Project Grant

Skeletal muscle wasting caused by nerve damage and disease, or by cancer, is a critical healthcare issue. Unsatisfactory treatments for these conditions are due, in part, to a lack of understanding of the molecular mechanisms responsible for muscle atrophy. We recently identified that a protein found in skeletal muscle named coactivator-associated arginine methyltransferase 1 (CARM1) is important for maintaining and remodelling muscle mass. Others have observed that inhibiting CARM1 activity with a new drug protects against tumor growth and extends lifespan in several rodent cancer models. Altogether, these exciting findings suggest that CARM1 is a modifiable component of skeletal muscle that may be an effective therapeutic target to reduce muscle atrophy in conditions of wasting and weakness. Thus, the goal of this proposal is to determine the molecular mechanisms of CARM1's role in the maintenance and plasticity of skeletal muscle mass and function. Using complementary genetic, pharmacological, and physiological strategies in adult mice we will identify the effects of inhibiting CARM1 activity throughout the whole body as compared to inhibiting its activity specifically in skeletal muscle, with specific focus on muscle mass and function during neurogenic- and cancer cachexia-induced atrophy. In addition, using similar experimental approaches we will further uncover the significance of the interactions between CARM1 and another powerful regulator of neuromuscular biology called AMPK. Moreover, we will employ profiling and bioinformatic tools to reveal novel CARM1-related pathways that regulate muscle mass, function, and atrophy. These studies are particularly timely as the experimental drugs to be investigated in this proposal are already in clinical trials for treating cancers and metabolic diseases. The results from this project will add fundamental knowledge about mechanisms regulating skeletal muscle mass and function, opening possibilities for new therapies.