Muscle-generated BDNF is a sexually dimorphic myokine that controls metabolic flexibility
Program in Molecular Medicine
Amino Acids, Peptides, and Proteins | Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry | Cellular and Molecular Physiology | Molecular Biology | Musculoskeletal System
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-1alpha 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.
DOI of Published Version
Sci Signal. 2019 Aug 13;12(594). pii: eaau1468. doi: 10.1126/scisignal.aau1468. Link to article on publisher's site
Yang X, Noh HL, Saengnipanthkul S, Kim JK, Lee CW, Chan CB. (2019). Muscle-generated BDNF is a sexually dimorphic myokine that controls metabolic flexibility. Program in Molecular Medicine Publications. https://doi.org/10.1126/scisignal.aau1468. Retrieved from https://escholarship.umassmed.edu/pmm_pp/133