Alpha1-syntrophin-deficient skeletal muscle exhibits hypertrophy and aberrant formation of neuromuscular junctions during regeneration.
Alpha1-syntrophin is a member of the family of dystrophin-associated proteins; it has been shown to recruit neuronal nitric oxide synthase and the water channel aquaporin-4 to the sarcolemma by its PSD-95/SAP-90, Discs-large, ZO-1 homologous domain. To examine the role of alpha1-syntrophin in muscle regeneration, we injected cardiotoxin into the tibialis anterior muscles of alpha1-syntrophin-null (alpha1syn-/-) mice. After the treatment, alpha1syn-/- muscles displayed remarkable hypertrophy and extensive fiber splitting compared with wild-type regenerating muscles, although the untreated muscles of the mutant mice showed no gross histological change. In the hypertrophied muscles of the mutant mice, the level of insulin-like growth factor-1 transcripts was highly elevated. Interestingly, in an early stage of the regeneration process, alpha1syn-/- mice showed remarkably deranged neuromuscular junctions (NMJs), accompanied by impaired ability to exercise. The contractile forces were reduced in alpha1syn-/- regenerating muscles. Our results suggest that the lack of alpha1-syntrophin might be responsible in part for the muscle hypertrophy, abnormal synapse formation at NMJs, and reduced force generation during regeneration of dystrophin-deficient muscle, all of which are typically observed in the early stages of Duchenne muscular dystrophy patients.
Hosaka
Yukio
Y
Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira 187-8502, Tokyo, Japan.
Yokota
Toshifumi
T
Miyagoe-Suzuki
Yuko
Y
Yuasa
Katsutoshi
K
Imamura
Michihiro
M
Matsuda
Ryoichi
R
Ikemoto
Takaaki
T
Kameya
Shuhei
S
Takeda
Shin'ichi
S
D000818:Animals; D051401:Aquaporin 4; D020346:Aquaporins / Q000032:analysis; D002135:Calcium-Binding Proteins; D004179:Cobra Cardiotoxin Proteins / Q000008:administration & dosage / Q000633:toxicity; D006984:Hypertrophy; D007273:Injections, Intramuscular; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000378:metabolism; D009469:Neuromuscular Junction / Q000033:anatomy & histology*; D005082:Physical Exertion / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D012038:Regeneration; D013002:Somatomedins / Q000032:analysis; D013997:Time Factors
C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D020346:Aquaporins; D002135:Calcium-Binding Proteins; D004179:Cobra Cardiotoxin Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D020033:Protein Isoforms; D013002:Somatomedins; C091825:syntrophin alpha1; D018995:Myosin Heavy Chains