BDNF is a mediator of glycolytic fiber-type specification in mouse skeletal muscle

Abstract

Brain-derived neurotrophic factor (BDNF) influences the differentiation, plasticity, and survival of central neurons and likewise, affects the development of the neuromuscular system. Besides its neuronal origin, BDNF is also a member of the myokine family. However, the role of skeletal muscle-derived BDNF in regulating neuromuscular physiology in vivo remains unclear. Using gain- and loss-of-function animal models, we show that muscle-specific ablation of BDNF shifts the proportion of muscle fibers from type IIB to IIX, concomitant with elevated slow muscle-type gene expression. Furthermore, BDNF deletion reduces motor end plate volume without affecting neuromuscular junction (NMJ) integrity. These morphological changes are associated with slow muscle function and a greater resistance to contraction-induced fatigue. Conversely, BDNF overexpression promotes a fast muscle-type gene program and elevates glycolytic fiber number. These findings indicate that BDNF is required for fiber-type specification and provide insights into its potential modulation as a therapeutic target in muscle diseases.

The Impact of Kinases in Amyotrophic Lateral Sclerosis at the Neuromuscular Synapse: Insights into BDNF/TrkB and PKC Signaling

“…Indeed, in normal mice, muscle-specific deletion of BDNF did not induce any change in NMJ integrity in healthy animals [105] nor did it have the same effect as TrkB disruption, which adversely affects NMJ structure and function [42,54,106,107]. This could decrease the importance of BDNF/TrkB signaling for maintaining NMJ function.…”

Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer

“…Therefore, it may also be involved in cancer, angiogenesis, reduction of glucose production from the liver [ 23 ], and in the uptake of glucose in peripheral tissues (see [ 24 ] for review). In addition, BDNF promotes the development of neuromuscular synapses and is required for fiber-type specification, suggesting a potential role as a therapeutic target in muscle diseases [ 25 ]. In this review, first we examine the currently known mechanisms of BDNF signaling, information essential for the creation of BDNF-based therapeutics.…”

ProNGF/p75NTR Axis Drives Fiber Type Specification by Inducing the Fast-Glycolytic Phenotype in Mouse Skeletal Muscle Cells

“…Among neurotrophins, BDNF is the most studied in the neuromuscular system. Indeed, this growth factor exerts pivotal physiological roles, facilitating the survival and the innervation pattern of motor neurons during development, regulating muscle regeneration, and affecting muscle strength [ 10 , 12 , 50 ]. Furthermore, recent findings also demonstrated the crucial involvement of BDNF signaling in the regulation of skeletal muscle metabolism and fiber type specification [ 12 , 51 ].…”

“…Indeed, this growth factor exerts pivotal physiological roles, facilitating the survival and the innervation pattern of motor neurons during development, regulating muscle regeneration, and affecting muscle strength [ 10 , 12 , 50 ]. Furthermore, recent findings also demonstrated the crucial involvement of BDNF signaling in the regulation of skeletal muscle metabolism and fiber type specification [ 12 , 51 ]. Concerning NGF, different studies highlighted a role in skeletal muscle physiology, with particular reference to the ability of this neurotrophin to modulate the regenerative capacity of myogenic precursors through the low-affinity receptor p75NTR [ 13 , 14 , 16 , 19 ].…”

“…The BDNF pathway has been particularly characterized in skeletal muscle, and a crucial involvement of this neurotrophin has been highlighted in neuromuscular junction structure, muscle regeneration, and myogenesis [ 9 , 10 , 11 ]. Interestingly, a very recent report indicated that BDNF could act as a autocrine/paracrine factor to transcriptionally mediate the fast/glycolytic program in muscle fibers [ 12 ]. Among neurotrophins, NGF seems to be particularly involved in muscle regeneration, although experimental evidence is still fragmented.…”