Halievski Katherine, Henley Casey L, Domino Laurel, Poort Jessica E, Fu Martina, Katsuno Masahisa, Adachi Hiroaki, Sobue Gen, Breedlove S Marc, Jordan Cynthia L
Neuroscience Program, Michigan State University, 293 Farm Lane, 108 Giltner, East Lansing, MI 48824-1101, USA.
Neuroscience Program, Michigan State University, 293 Farm Lane, 108 Giltner, East Lansing, MI 48824-1101, USA.
Exp Neurol. 2015 Jul;269:224-32. doi: 10.1016/j.expneurol.2015.04.013. Epub 2015 Apr 27.
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 muscles 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 skeletal muscle may have therapeutic value for SBMA.
已发现神经营养因子在骨骼肌中的转基因表达可保护小鼠免受神经肌肉疾病的侵害，包括脊髓延髓肌肉萎缩症（SBMA），这引发了人们对神经营养因子作为治疗神经肌肉疾病药物的新兴趣。由于SBMA是一种雄激素依赖性疾病，且脑源性神经营养因子（BDNF）介导雄激素对神经肌肉系统的作用，我们研究了在两种不同的SBMA转基因（Tg）小鼠模型，即所谓的“97Q”和“肌源性”SBMA模型中，BDNF的表达是否受损。97Q模型全局过表达具有97个谷氨酰胺重复序列的全长人雄激素受体（AR），而SBMA的肌源性模型仅在骨骼肌纤维中过表达野生型大鼠雄激素受体（AR）。使用定量PCR，我们发现两种模型中肌肉BDNF mRNA均以雄激素依赖性方式下降，这与运动功能的变化平行，受损Tg雄性小鼠的快肌和慢肌中均存在明显缺陷（6 - 8倍）。去势可挽救或逆转两种模型中与疾病相关的肌肉BDNF mRNA缺陷，这与其对运动功能的影响平行。此外，当在Tg雌性小鼠中急性诱发疾病时，运动功能和肌肉BDNF mRNA表达均急剧下降，肌肉BDNF的缺陷在明显的运动功能障碍之前就已出现。雄激素依赖性运动功能障碍与肌肉BDNF mRNA的强烈且早期下调紧密相关，这表明输送到骨骼肌的BDNF可能对SBMA具有治疗价值。
