Abstract

Disuse osteoporosis (DOP), a skeletal disorder triggered by insufficient mechanical loading, manifests as progressive bone mass deterioration and microarchitectural weakening. Piezo1, a key mechanosensitive ion channel expressed in bone cells, is implicated in maintaining skeletal homeostasis. Using a murine hindlimb unloading (HLU) model simulating microgravity-induced bone loss, we observed significant downregulation of Piezo1 expression in bone tissue and isolated bone marrow-derived mesenchymal stem cells (BMSCs). Systemic administration of the Piezo1 agonist Yoda1 attenuated HLU-induced osteopenia and improved bone formation capacity. Mechanistic studies in BMSCs demonstrated that Piezo1 activation promoted mitochondrial biogenesis. This effect required AMPK/SIRT1 signaling-dependent deacetylation of PGC-1α, leading to enhanced mitochondrial function, improved osteogenic differentiation, and reduced apoptosis. Critically, pharmacologic inhibition of SIRT1 abolished the osteoprotective effects of Yoda1 in vivo. These findings establish that mechanical unloading impairs Piezo1-mediated mechanotransduction in BMSCs, contributing to disrupted skeletal homeostasis, which can be mitigated by exogenous Piezo1 activation. Our results define a mechanism where Piezo1 integrates mechanical signals into the AMPK/SIRT1/PGC-1α signaling cascade to regulate mechanoadaptive bone formation, highlighting Piezo1 activation as a potential mechanism-based therapeutic strategy for disuse osteoporosis.