Abstract
Musculoskeletal diseases, such as osteoporosis and sarcopenia, are tremendous and growing public health concerns. Considering the intimate functional relationship between muscle and bone throughout development, growth, and aging, muscle provides the primary source of skeletal loading through contraction force. However, significant gaps exist in our knowledge regarding the role of muscle in bone homeostasis and little is known regarding the mechanism through which the central nervous system responds and regulates unloading-induced bone loss. Here, we showed that the basolateral amygdala (BLA) and medial part of the central nucleus (CeM) are anatomically connected with the musculoskeletal system. Unloading-induced bone loss is accompanied by a decrease in serum semaphorin 3A (Sema3A) levels as well as sensory denervation. In vivo fiber photometry recordings indicated that the mechanical signal is integrated by the BLA and CeM within 24 h and subsequently regulates bone remodeling. Moreover, chemogenetic activation of BLACaMKII neurons mitigates severe bone loss caused by mechanical unloading via increased serum levels of Sema3A and sensory innervation. These results indicate that the BLA integrates the mechanosensory signals rapidly and mediates the systemic hormonal secretion of Sema3A to maintain bone homeostasis.
Highlights
The musculoskeletal system plays an important role in maintaining the function of body locomotion and metabolic homeostasis, and is composed of skeletal muscles, bones, connective tissues, nerves, and blood vessels
To investigate the neural mechanism by which mechanical loading enables bone homeostasis, we recruited an animal model of transient hindlimb muscle paralysis induced by botulinum toxin type A (BTxA), which can block muscle-derived force generated by muscle contraction (Figure 1A)
Following intramuscular injection of BTxA, our results showed rapid muscle and bone degradation in response to acute muscle paralysis, with significantly decreased muscle wet mass and fiber size (Figures 1B,C) as well as trabecular (−27.3%, P < 0.01) and cortical bone mineral density (BMD) (−3.1%, P < 0.01) (Figures 1E,J)
Summary
The musculoskeletal system plays an important role in maintaining the function of body locomotion and metabolic homeostasis, and is composed of skeletal muscles, bones, connective tissues, nerves, and blood vessels. Muscle atrophy and bone loss are associated with a variety of mechanical milieu, including advanced aging, sedentary lifestyle, spinal cord injury, and microgravity (Lang et al, 2004; Trappe et al, 2009; Qin et al, 2010; Steffl et al, 2017; GarrettBakelman et al, 2019). In these mechanical contexts, muscle atrophy always precedes bone loss, and recovers faster than bone after restoration of mechanical loading (Lloyd et al, 2014). As a hypersensitive mechanosensory organ, how decreased skeletal loading affects bone cannot be fully explained by traditional mechanistic theories linking muscle function and bone morphology and the systemic regulation by which muscle enables bone homeostasis remains largely elusive
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