Aging-Related Muscle Bmal1 Decline Contributes to Bone Loss in Mice via Enhancing IL-1α-Mediated Osteoclastogenesis

Osteoporosis, a common metabolic bone disorder linked to aging, is often accompanied by muscle degeneration. Muscle Bmal1 disruption in mice has been shown to affect various tissues, including the kidney, lung, and bone, indicating that the muscle molecular clock may influence the physiological homeostasis of multiple organs through systemic circulation. Despite this, the role of the muscle clock in age-related osteoporosis remains unclear. In aged mice, we observed a disruption in the circadian interaction between muscle and bone. Furthermore, both Bmal1 expression within muscle fibers and total BMAL1 protein levels in muscle tissue were significantly reduced. Using skeletal muscle-specific Bmal1 knockout mice, we observed osteoporosis-related phenotypes, including decreased bone mass and disrupted trabecular microarchitecture, along with disrupted diurnal expression of inflammatory cytokines. Mechanistically, we revealed that muscle Bmal1 deficiency impairs the rhythmic expression of the Hmox1 and induces the upregulation of IL-1α in muscle cells. The elevated circulating IL-1α promotes osteoclast differentiation, ultimately reducing bone mass. Importantly, the osteoporosis-related phenotype resulting from muscle Bmal1 knockout or aging was alleviated by nighttime time-restricted feeding (TRF), which reestablished a feeding-driven diurnal variation in Hmox1 expression within the muscle and reduced serum IL-1α levels. This study provides new insights into the pathogenesis of osteoporosis in the aging population. Furthermore, it suggests that TRF may offer a promising therapeutic strategy for treating osteoporosis in the elderly.