Androgen-dependent loss of muscle BDNF mRNA in two mouse models of SBMA

Abstract

Transgenic expression of neurotrophic factors in skeletal muscle has been found to protect mice from neuromuscular disease, including spinal bulbar muscular atrophy (SBMA), triggering renewed interest in neurotrophic factors as therapeutic agents for treating neuromuscular disease. Because SBMA is an androgen-dependent disease, and brain-derived neurotrophic factor (BDNF) mediates effects of androgens on neuromuscular systems, we asked whether BDNF expression is impaired in two different transgenic (Tg) mouse models of SBMA, the so called “97Q” and “myogenic” SBMA models. The 97Q model globally overexpresses a full length human AR with 97 glutamine repeats whereas the myogenic model of SBMA overexpresses a wild-type rat androgen receptor (AR) only in skeletal muscle fibers. Using quantitative PCR, we find that muscle BDNF mRNA declines in an androgen-dependent manner in both models, paralleling changes in motor function, with robust deficits (6-8 fold) in both fast and slow twitch muscle of impaired Tg males. Castration rescues or reverses disease-related deficits in muscle BDNF mRNA in both models, paralleling its effect on motor function. Moreover, when disease is acutely induced in Tg females, both motor function and muscle BDNF mRNA expression plummet, with the deficit in muscle BDNF emerging before overt motor dysfunction. That androgen-dependent motor dysfunction is tightly associated with a robust and early down-regulation of muscle BDNF mRNA suggests that BDNF delivered to muscle may have therapeutic value for SBMA.

Disease Affects Bdnf Expression in Synaptic and Extrasynaptic Regions of Skeletal Muscle of Three SBMA Mouse Models

“…Our next goal was to examine mRNA expression for the neurotrophins—nerve growth factor (NGF, Ngf ), brain-derived neurotrophic factor (BDNF, Bdnf ), neurotrophin-4/5 (NT-4, Ntf5 ), and neurotrophin-3 (NT-3, Ntf3 ). As found previously, whole muscle expression of both Bdnf [22] and Ntf5 [6] were affected by disease and we now show that this indeed occurs in both domains (Figure 2a,c). Moreover, both neurotrophic factors were expressed uniformly across muscle domains in WT and diseased mice (Figure 2b,d).…”

“…Using quantitative real-time PCR, we examined the expression of a number of genes with known function. Our primary interest was in the neurotrophic factors, since such factors are implicated in SBMA and are critical for proper synaptic and muscle function, both of which are profoundly impaired in models of SBMA [5,6,10,11,14,15,22,23,24,25,26,27,28]. While skeletal muscles are well known to express numerous neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and other related neurotrophins, it not known whether their expression is regionally regulated across the length of the fiber, particularly in the context of neuromuscular disease.…”

Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes

“…Clenbuterol exerts trophic effects on motor neurons, which are sensitive to changes in the generation and release of neurotrophins, such as brain-derived neurotrophic factor (BDNF). Notably, BDNF levels are decreased in SBMA muscle48. BDNF has been shown to promote local protein synthesis to improve synaptic strength and function and to ameliorate axonal transport defects in SBMA49.…”

Non-Cell-Autonomous Regulation of Retrograde Motoneuronal Axonal Transport in an SBMA Mouse Model

“…Skeletal muscle releases many kinds of trophic factors that can act on receptors in motor nerve terminals to promote healthy cell function. Diseased muscle from various SBMA mouse models exhibits deficits in multiple trophic factors, including brain-derived neurotrophic factor (BDNF), glial cell line-derived factor, insulin-like growth factor 1, neurotrophin (NT)-4, and vascular endothelial growth factor (VEGF) ( Sopher et al, 2004 ; Yu et al, 2006 ; Monks et al, 2007 ; Mo et al, 2010 ; Halievski et al, 2015 ). Moreover, replenishing the supply of such neurotrophic factors can reverse disease-related deficits in axonal transport in models of motoneuron/neuromuscular disease.…”