Androgen-dependent loss of muscle BDNF mRNA in two mouse models of SBMA.
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.
Neuroscience Program, Michigan State University, 293 Farm Lane, 108 Giltner, East Lansing, MI 48824-1101, USA. Electronic address: halievsk@msu.edu.
Katherine
K
Halievski
Neuroscience Program, Michigan State University, 293 Farm Lane, 108 Giltner, East Lansing, MI 48824-1101, USA.
Casey L
CL
Henley
Neuroscience Program, Michigan State University, 293 Farm Lane, 108 Giltner, East Lansing, MI 48824-1101, USA.
Laurel
L
Domino
Neuroscience Program, Michigan State University, 293 Farm Lane, 108 Giltner, East Lansing, MI 48824-1101, USA.
Jessica E
JE
Poort
Neuroscience Program, Michigan State University, 293 Farm Lane, 108 Giltner, East Lansing, MI 48824-1101, USA.
Martina
M
Fu
Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Masahisa
M
Katsuno
Department of Neurology, University of Occupational and Environmental Health School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan.
Hiroaki
H
Adachi
Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Gen
G
Sobue
Neuroscience Program, Michigan State University, 293 Farm Lane, 108 Giltner, East Lansing, MI 48824-1101, USA.
S Marc
SM
Breedlove
Neuroscience Program, Michigan State University, 293 Farm Lane, 108 Giltner, East Lansing, MI 48824-1101, USA.
Cynthia L
CL
Jordan
D000728:Androgens / Q000378:metabolism*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D011944:Receptors, Androgen / Q000276:immunology / Q000378:metabolism
D000728:Androgens; D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D011944:Receptors, Androgen
Motoneuron disease; Neurodegenerative disease; Neuromuscular disease; Neurotrophic factor; Neurotrophin