Skeletal muscle mitochondrial dysfunction in mice is linked to bone loss via the bone marrow immune microenvironment.

Abstract

Mitochondrial oxidative phosphorylation (OxPhos) is a critical regulator of skeletal muscle mass and function. Although muscle atrophy due to mitochondrial dysfunction is closely associated with bone loss caused by reduction of mechanical loading, questions remain about the biological characteristics in the relationship between muscle and bone. Here, we have shown that muscle atrophy caused by skeletal muscle-specific Crif1 knockout (MKO) modulates the bone marrow inflammatory response, leading to bone loss. Transcriptome analysis of the extensor digitorum longus revealed that local mitochondrial stress increased serum levels of fibroblast growth factor 21 (FGF21) in mice. However, we have shown by Fgf21 knockout in MKO mice that FGF21 is dispensable for muscle atrophy-mediated bone loss. RNA sequencing in MKO mice indicated that mitochondrial stress response in skeletal muscles induces an inflammatory response and adipogenesis in the bone marrow. We also found, using transcriptomic analysis of bone marrow, that the CXCL12-CXCR4 axis is important for T-cell homing to the bone marrow, which is an immunological mediator of muscle-bone communication. CXCR4 antagonism attenuated bone marrow inflammation and bone loss in MKO mice. Together, these data highlight the role that muscle mitochondrial dysfunction plays in triggering bone marrow inflammation via the CXCL12-CXCR4 signaling axis, which is critical for inducing bone loss.