Project 434367

Glucocorticoids are one of the most widely prescribed classes of drugs in both children and adults due to their potent anti-inflammatory action. However, one of the major side effects of glucocorticoid treatment is muscle atrophy, a condition where muscle mass is lost. Despite the side effects, for boys suffering from Duchenne muscular dystrophy (DMD), a muscle wasting disease, glucocorticoids are the first line of treatment, preventing disease worsening for up to three years. While glucocorticoids remain the best treatment for many conditions, little is known about how glucocorticoids cause muscle atrophy as a side effect or paradoxically improve the disease course of DMD. Since the maintenance of muscle mass is dependent on the activity of muscle stem cells, which are essential for muscle regeneration, it is critical to understand how glucocorticoids affect these cells and their activity. To understand how glucocorticoids act on muscle stem cells, we made a mouse model where muscle stem cells cannot respond to glucocorticoids. We found that glucocorticoids are important during muscle repair as they act to organize the muscle fiber's contraction machinery and to correctly position cell nuclei. We predict that glucocorticoids alter the structure of the cytoskeleton, a fibrous protein latticework inside the muscle cell that gives it its shape and ability to resist mechanical stress. In diseased muscle, like in DMD patients, we think glucocorticoids improve the cytoskeleton by making the connections more square and less random, which protects the cell from contraction-induced injury. In healthy muscle, we think glucocorticoids make the cytoskeleton too rigid and inflexible, and this causes the damage we see as atrophy. To study this, we will use molecular and cell biology techniques to determine how glucocorticoids exert their actions in newly formed muscle fibers and their effects on normal and wasting muscle.