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

Exp Neurol. 2015 Jul:269:224-32. doi: 10.1016/j.expneurol.2015.04.013. Epub 2015 Apr 27.

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 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.

Keywords: Motoneuron disease; Neurodegenerative disease; Neuromuscular disease; Neurotrophic factor; Neurotrophin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / metabolism*
  • Animals
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Disease Models, Animal
  • Mice
  • Mice, Transgenic
  • Motor Neurons / metabolism
  • Muscle, Skeletal / metabolism*
  • Muscular Atrophy / metabolism*
  • Muscular Atrophy, Spinal / metabolism
  • RNA, Messenger / metabolism*
  • Rats
  • Receptors, Androgen / immunology
  • Receptors, Androgen / metabolism

Substances

  • Androgens
  • Brain-Derived Neurotrophic Factor
  • RNA, Messenger
  • Receptors, Androgen