Muscle-derived Mimecan regulates hypothalamus-brown adipose tissue communication and promotes health and lifespan in mice

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. • Muscle-derived Mimecan regulates core body temperature via brown adipose tissue • Mimecan activates MC4R-positive neurons in the DMH/DHA via maintaining primary cilia • Restoring plasma Mimecan levels counteracts aging and promotes lifespan in aged mice • Voluntary exercise improves core body temperature regulation via maintaining Mimecan Mori and Imai demonstrate that skeletal muscle-derived Mimecan regulates the inter-organ communication between hypothalamus, skeletal muscle, and brown adipose tissue by activating a specific subset of neurons in the hypothalamus. Restoring circulating Mimecan levels counteracts aging and promotes lifespan in aged mice, and voluntary exercise can maintain circulating Mimecan levels.