Muscle-generated BDNF is a sexually dimorphic myokine that controls metabolic flexibility

Xiuying Yang, Daniel Brobst, Wing Suen Chan, Margaret Chui Ling Tse, Oana Herlea-Pana, Palak Ahuja, Xinyi Bi, Aung Moe Zaw, Zara Sau Wa Kwong, Wei-hua Jia, Zhong-gou Zhang, Ning Zhang, Simon Kwoon Ho Chow, Wing Hoi Cheung, Jimmy Chun Yu Louie, Timothy M. Griffin, Wenyan Nong, Jerome Ho Lam Hui, Guan-hua Du, Hye Lim NohSuchaorn Saengnipanthkul, Billy K. C. Chow, Jason K. Kim, Chi Wai Lee*, Chi Bun Chan*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

43 Citations (Scopus)

Abstract

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-1α 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.
Original languageEnglish
Article numbereaau1468
JournalScience Signaling
Volume12
Issue number594
DOIs
Publication statusPublished - Aug 2019

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