期刊
SCIENCE SIGNALING
卷 12, 期 594, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aau1468
关键词
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资金
- Presbyterian Health Foundation (PHF) Seed Grant Program
- HKU Research Committee Seed Funding Programme for Basic Research [201606159006]
- Hong Kong Government Research Grant Council [GRF17113817]
- National Natural Science Foundation of China [NSFC 81470159]
- CAMS Initiative for Innovative Medicine [CAMS-I2M 2016-I2M-3-007]
- Drug Innovation Major Project [2018ZX09711001-003-005]
- NIH [5U2C-DK093000]
The ability of skeletal muscle to switch between lipid and glucose oxidation for ATP production during metabolic stress is pivotal for maintaining systemic energy homeostasis, and dysregulation of this metabolic flexibility is a dominant cause of several metabolic disorders. However, the molecular mechanism that governs fuel selection in muscle is not well understood. Here, we report that brain-derived neurotrophic factor (BDNF) is a fasting-induced myokine that controls metabolic reprograming through the AMPK/CREB/PGC-1 alpha pathway in female mice. Female mice with a muscle-specific deficiency in BDNF (MBKO mice) were unable to switch the predominant fuel source from carbohydrates to fatty acids during fasting, which reduced ATP production in muscle. Fasting-induced muscle atrophy was also compromised in female MBKO mice, likely a result of autophagy inhibition. These mutant mice displayed myofiber necrosis, weaker muscle strength, reduced locomotion, and muscle-specific insulin resistance. Together, our results show that muscle-derived BDNF facilitates metabolic adaption during nutrient scarcity in a gender-specific manner and that insufficient BDNF production in skeletal muscle promotes the development of metabolic myopathies and insulin resistance.
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