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

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.

Sex-Specific Associations of Brain-Derived Neurotrophic Factor and Cardiorespiratory Fitness in the General Population

“…Interestingly, BDNF was recently identified to regulate and promote a glycolytic muscle fiber phenotype in young male mice [27]. However, in female mice, a lack of BDNF resulted in skeletal muscle metabolic myopathy and insulin resistance [28]. Further research is required to confirm and fully understand potential sex-specific associations and their underlying mechanisms between cardiorespiratory fitness, skeletal muscle function, and BDNF.…”

“…Hence, these parameters were included as confounders. Further, very recently, BDNF was identified as sexually dimorphic neurotrophin [27,28].…”

Crosstalk between the muscular estrogen receptor α and BDNF/TrkB signaling alleviates metabolic syndrome via 7,8-dihydroxyflavone in female mice

“…Yang et al. [ 32 ] revealed that muscle-derived BDNF acts as a myokine and plays an important role in controlling energy metabolism. However, the clinical application of BDNF is greatly limited by its short half-life and non-bioavailable nature [ 33 ].…”

Effects of fasting on the expression pattern of FGFs in different skeletal muscle fibre types and sexes in mice

“…During fasting or energy deficits, the skeletal muscles would adjust energy demands and preserve energy homeostasis [12]. Ours and other studies found that growth factors coordinate metabolic reprogramming in muscle during fasting [13].…”