Research ArticleMetabolism

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

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Science Signaling  13 Aug 2019:
Vol. 12, Issue 594, eaau1468
DOI: 10.1126/scisignal.aau1468

Engendering metabolically flexible muscle

The effect of gender differences on many physiological processes, including metabolism, is an understudied area. Although BDNF is best known as a neurotrophin involved in synaptic plasticity and neuronal survival, Yang et al. found that fasting triggered the production of BDNF from skeletal muscle in female mice but not in male mice. During fasting, skeletal muscles switch from using carbohydrates to fatty acids as a fuel source. Skeletal muscle deficiency of BDNF in female mice (but not in male mice) prevented this metabolic switch and resulted in myofiber necrosis, reduced muscle strength, and insulin resistance. Therefore, BDNF production by skeletal muscle enables metabolic adaption during fasting in female mice.

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.

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