Angiotensin II receptor blockade promotes repair of skeletal muscle through down-regulation of aging-promoting C1q expression

Disruption of angiotensin II type 1 (AT₁) receptor prolonged life span in mice. Since aging-related decline in skeletal muscle function was retarded in Atgr1a^−/− mice, we examined the role of AT₁ receptor in muscle regeneration after injury. Administration of AT₁ receptor blocker irbesartan increased the size of regenerating myofibers, decreased fibrosis and enhanced functional muscle recovery after cryoinjury. We recently reported that complement C1q, secreted by macrophages, activated Wnt/β-catenin signaling and promoted aging-related decline in regenerative capacity of skeletal muscle. Notably, irbesartan induced M2 polarization of macrophages, but reduced C1q expression in cryoinjured muscles and in cultured macrophage cells. Irbesartan inhibited up-regulation of Axin2, a downstream gene of Wnt/β-catenin pathway, in cryoinjured muscles. In addition, topical administration of C1q reversed beneficial effects of irbesartan on skeletal muscle regeneration after injury. These results suggest that AT₁ receptor blockade improves muscle repair and regeneration through down-regulation of the aging-promoting C1q-Wnt/β-catenin signaling pathway.