Muscle-derived Mimecan regulates hypothalamus-brown adipose tissue communication and promotes health and lifespan in mice.
Abstract
Inter-organ communication plays a critical role in mammalian aging and longevity control. Here, we identified Mimecan from transcriptomic comparisons between young and aged skeletal muscles. Skeletal muscle-derived Mimecan regulates core body temperature via brown adipose tissue (BAT), which is impaired in aged mice. Skeletal muscle-specific loss- and gain-of-function models demonstrate that Mimecan activates melanocortin 4 receptor (MC4R)-positive neurons in the dorsomedial hypothalamus (DMH) and dorsal hypothalamic area (DHA) via maintaining primary cilia in those neurons, enhancing the sympathetic nervous tone directed to BAT. Furthermore, DMH/DHA-specific Mc4r-knockdown completely abolishes the effect of Mimecan overexpression on BAT function. Lastly, the restoration of Mimecan levels in blood circulation significantly extends lifespan in aged mice, suggesting that Mimecan plays a critical role in counteracting aging and promoting lifespan. Taken together, this study demonstrates the importance of inter-organ communication between the hypothalamus, skeletal muscle, and BAT in the systemic regulation of mammalian aging and longevity.
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Research summary
Mimecan secreted by skeletal muscle extends lifespan in aged mice by activating hypothalamic MC4R neurons to enhance sympathetic tone to brown adipose tissue. This study provides mechanistic evidence for a specific inter-organ signaling pathway that counteracts aging phenotypes, representing a solid but incremental advance in understanding the molecular basis of longevity.
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