Muscle BDNF improves synaptic and contractile muscle strength in Kennedy's disease mice in a muscle‐type specific manner

Abstract

Muscle-derived neurotrophic factors may offer therapeutic promise for treating neuromuscular diseases.r We report that a muscle-derived neurotrophic factor, BDNF, rescues synaptic and muscle function in a muscle-type specific manner in mice modelling Kennedy's disease (KD).r We also find that BDNF rescues select molecular mechanisms in slow and fast muscle that may underlie the improved cellular function.r We also report for the first time that expression of BDNF, but not other members of the neurotrophin family, is perturbed in muscle from patients with KD.r Given that muscle BDNF had divergent therapeutic effects that depended on muscle type, a combination of neurotrophic factors may optimally rescue neuromuscular function via effects on both pre-and postsynaptic function, in the face of disease.

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 ].…”

Muscle BDNF: a potential therapeutic target for Kennedy's disease

“…In conclusion, the Halievski et al . 2020 paper reports important findings suggesting for the first time that muscle BDNF may delay disease onset and endpoint in the 97Q mouse model of KD. While these findings are promising, further preclinical work in the 97Q mouse and other mouse models of KD should be pursued to determine if muscle BDNF can play a further role in treating KD.…”

“…BDNF is also expressed and released by skeletal muscle in response to contraction. Muscle-derived BDNF is thought to regulate local muscular development through increased protein synthesis and neuromuscular synaptic transmission (Kowianski et al 2018;Halievski et al 2020). BDNF expression is higher in more oxidative (type I) slow-twitch muscle such as the soleus, in comparison to fast-twitch glycolytic (type II) fibres (Just-Borras et al 2019).…”

“…Given the expression, location and synaptic role of BDNF in muscle, it has potential for rescuing dysfunctional neuromuscular transmission observed in KD. Herein lies the novelty of the paper by Halievski et al 2020 published in a recent issue of The Journal of Physiology, which provides insight into the role of muscle-derived BDNF in KD and its therapeutic potential. We highlight their findings here while discussing a potential effect of muscle BDNF on fibre type shifts during neuromuscular disease states and ways in which this could be used as a therapeutic strategy.…”

“…2018; Halievski et al . 2020). BDNF expression is higher in more oxidative (type I) slow‐twitch muscle such as the soleus, in comparison to fast‐twitch glycolytic (type II) fibres (Just‐Borras et al .…”