The Glucocorticoid Receptor Regulates Myonuclear Positioning During Skeletal Muscle Differentiation

Abstract

Proper myonuclear positioning is essential for skeletal muscle function and relies on the coordination of the nucleoskeleton, cytoskeleton, and the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. Although glucocorticoids are widely used therapeutically to treat muscular dystrophies, the muscle-intrinsic mechanisms underlying their effects on improving muscle strength remain unclear. Here, we investigate the role of the glucocorticoid receptor in regulating myonuclear positioning during myogenic differentiation and skeletal muscle regeneration. Pharmacological inhibition of the glucocorticoid receptor (GR) with RU-486 in C2C12 myotubes or knockdown of GR expression in vivo resulted in disrupted nuclear alignment. Mechanistically, GR inhibition decreased the levels of Lamin A and SUN1 proteins within the soluble fraction. This, in turn, disrupted the alignment of pericentrin and the Golgi apparatus to the nuclear envelope, ultimately disorganizing the microtubule network. Together, these data identify GR as a critical regulator of myonuclear positioning and of nuclear-cytoskeletal integrity during muscle differentiation, providing mechanistic insight into how glucocorticoid therapies may improve muscle function in patients with muscular dystrophies.