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Sci Signal. 2019 Aug 13;12(594). pii: eaau1468. doi: 10.1126/scisignal.aau1468.

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

Author information

1
Department of Physiology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., BMSB 634, Oklahoma City, OK 73104, USA.
2
State Key Laboratory of Bioactive Substance and Function of Natural Medicines and Beijing Key Laboratory of Drug Target and Screening Research, Institute of Materia Medica of Peking Union Medical College, Beijing 100050, China.
3
School of Biological Sciences, The University of Hong Kong, 6N01 Kadoorie Biological Sciences Building, Pokfulam Road, Hong Kong.
4
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
5
Department of Chemical Engineering, University of Waterloo, ON N2L 3G1, Canada.
6
Department of Colorectal Cancer Oncological Surgery, Large-Scale Data Analysis Center of Cancer Precision Medicine, Cancer Hospital of Chinese Medical University, Liaoning Provincial Cancer Institute and Hospital, Shenyang 110042, China.
7
Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, 5/F Lui Che Woo Clinical Sciences Building, Prince of Wales Hospital, Shatin, Hong Kong.
8
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
9
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
10
School of Life Sciences, Chinese University of Hong Kong, Shatin, Hong Kong.
11
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
12
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong. chancb@hku.hk chiwai.lee@hku.hk.
13
School of Biological Sciences, The University of Hong Kong, 6N01 Kadoorie Biological Sciences Building, Pokfulam Road, Hong Kong. chancb@hku.hk chiwai.lee@hku.hk.
14
State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong.

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.

PMID:
31409756
DOI:
10.1126/scisignal.aau1468

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