Skeletal muscle wasting and reduced muscle quality are critical features of cancer cachexia that contribute to poor outcomes and reduced survival in patients with cancer. Myocilin, a pro-hypertrophic protein that also stabilizes the muscle fiber membrane, was found to be reduced in skeletal muscle in multiple models of cancer cachexia and in muscle biopsies of cancer patients defined as cachectic. Using mice lacking Myocilin, it was found that loss of Myocilin alone is sufficient to induce features of cancer cachexia, including skeletal muscle fiber atrophy and infiltration of muscle with fat and fibrotic tissue. In mouse models of cancer cachexia, Myocilin gain of function attenuated skeletal muscle wasting, while targeting its immediate upstream activator, myocyte enhancer factor 2c (MEF2c), also deterred both muscle wasting and muscle dysfunction. For details, see article by Judge and colleagues on page 1861.