YAP1‐Driven Pathogenic Fibro‐Adipogenic Progenitors Secrete IL‐6 and FGF21 to Mediate Muscle‐Bone Crosstalk and Promote Bone Loss

Sarcopenia, an age-related degenerative disease of skeletal muscle, is closely associated with osteoporosis and other bone disorders, partly due to dysregulated endocrine function of skeletal muscle. However, the specific cellular sources and molecular mechanisms driving this pathological secretory phenotype remain poorly defined. Using three distinct aging murine models, including sedentary controls, treadmill exercise-trained (TE) mice, and botulinum toxin A (BTXA)-induced muscle atrophy, combined with human cohort analysis, we investigated muscle-bone crosstalk. Fluorescence-activated cell sorting (FACS) was used to isolate fibro-adipogenic progenitors (FAPs). FAP-specific genetic manipulations, including conditional knockout (cKO) mice and adeno-associated virus-mediated knockdown, together with pharmacological inhibition of YAP1, were employed to dissect the mechanistic link between muscle secretory dysfunction and bone metabolism. We demonstrate that pathogenic activation of FAPs serves as a critical cellular source of bone-catabolic myokines during muscle atrophy. In a human cohort of older individuals with sarcopenia, osteoporosis, or osteosarcopenia, FAP numbers were significantly increased and correlated positively with sarcopenia traits and IL-6 and FGF21 levels. In mice, muscle wasting drives FAP accumulation through YAP1-mediated mechanotransduction, characterized by enhanced proliferation, suppressed apoptosis, and acquisition of a profibrotic phenotype concomitant with elevated IL-6 and FGF21 secretion. Using FAP-specific Il6 or Fgf21 knockdown, we showed that genetic ablation of these myokines in FAPs rescued trabecular bone loss despite persistent muscle atrophy. Mechanistically, YAP1 functions as a central regulator of this pathogenic secretory phenotype; FAP-specific Yap1 overexpression may contribute to the myokine dysfunction and bone loss, while FAP-specific Yap1 deletion or pharmacological inhibition diminished bone-loss-related myokine production and ameliorated bone deterioration. FAP-specific Yap1 cKO mice demonstrated that endogenous YAP1 is essential for pathogenic FAP activation and subsequent bone loss. Furthermore, therapeutic targeting of the FAP-YAP1-myokine axis provided robust skeletal protection in ovariectomy-induced postmenopausal osteoporosis. These findings reveal that dysregulated endocrine function of skeletal muscle promotes bone loss through YAP1-driven pathogenic FAPs secreting IL-6 and FGF21, identifying FAP-derived IL-6 and FGF21 as key mediators of muscle-bone crosstalk and establishing the YAP1-FAP-myokine axis as a therapeutic target for preventing bone loss in sarcopenia and osteoporosis.