Sympathetic innervation maintains the murine quiescent skeletal muscle stem cell pool via perivascular-derived Angpt1

Abstract

Muscle stem cells rely on their niche for maintenance, yet how β-adrenergic innervation regulates these cells remains elusive. Here, we show that sympathetic fibers in skeletal muscle innervate the vascular stem cell niche, specifically targeting β-adrenergic receptors on perivascular cells. We observe that sympathetic denervation leads to vascular remodeling and, concomitantly, reduces the muscle stem cell pool, resulting in tissue repair defects. Mechanistically, we demonstrate that sympathetic denervation reduces perivascular-derived angiopoietin-1, a crucial factor in maintaining the quiescent state of post-natal muscle stem cells. Using pharmacologic and genetic tools, we identify that sympathetic signaling drives angiopoietin-1 production from murine perivascular cells through the stimulation of their β-adrenergic receptors, thereby preserving the quiescent stem cell pool. Collectively, our data identify the molecular and cellular axis coupling skeletal muscle tissue homeostasis and regeneration to sympathetic innervation and β-adrenergic signaling, which are thus key signaling pathways that contribute to satellite cell quiescence.