Research on muscular dystrophy using mouse developmental biotechnology

2000 Fiscal Year Final Research Report Summary

• Project/Area Number: 10670150
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: SASAOKA Toshikuni National Institute of Neuroscience, Section Chief, 神経研究所, 室長 (50222005)
• Project Period (FY): 1998 – 2000
• Keywords: Mouse / Developmental biotechnology / Muscular dystrophy / Muscle hypertrophy / Sarcoglycan / Dystrophin / Dystroglycan / Model animal

Research Abstract

Sarcoglycanopathy (SGP) is similar to Duchenne muscular dystrophy (DMD) with respect to clinical features and muscle pathology, except for its mode of inheritance, slightly later onset in most cases, less frequent cardiac involvement, absence of mental impairment, and slightly slower progression. The four sarcoglycan subunits (α-, β-, γ-, and δ-SG) of the sarcoglycan complex (SGC) have been shown in four respective forms of SGP.
To analyze the physiological roles of the individual subunits of SGC and elucidate the pathogenetic mechanisms of muscle hypertrophy and degeneration, we generated γ-SG-deficient (GSG-/-) mice by gene targeting. The limb, shoulder, and pelvic muscles of the GSG-/- mice exhibited progressive muscle hypertrophy and weakness with age, and findings were similar to those seen in other mouse models for limb girdle and DMD.While calf muscle hypertrophy is a striking diagnostic finding in DMD and SGP, its pathogenetic mechanism remains unknown. We found that the number of muscle fibers in tibialis anterior muscle increased with age, and most of the fibers in the hypertrophic muscle were centrally nucleated regenerating fibers. Fiber branching was seen in hypertrophied muscle. Therefore, muscle hypertrophy may represent a consequence of extensive fiber branching and an increase of muscle fibers. Muscle hypertrophy is not due to fibrous and fat tissue replacement, as has been shown to be the case in the so-called pseudohypertrophy in muscle diseases in humans. The muscle pathology became more "dystrophic" in mice over one year of age when there was a marked variation in fiber size with interstitial fibrosis.

Research Products

• [Publications] Yasuko Hagiwara et al.: "Caveolin-3 deficiency causes muscle degeneration in mice."Human Molecular Genetics. Vol.9(20). 3047-3054 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Mikiharu Yoshida et al.: "Biochemical evidence for association of dystrobrevin with the sarcoglycansarcospan complex as a basis for understanding sarcoglycanopathy."Human Molecular Genetics. Vol.9(7). 1033-1040 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Yanyan Wang et al.: "Dopamine D2Long receptor-deficient mice display hypolocomotion and reduced level of haloperidol-induced catalepsy."Journal of Neuroscience. Vol.20(22). 8305-8314 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Hagiwara, Y, Sasaoka, T, Araishi K, Imamura M, Yorifuji, H, Nonaka, I, Ozawa E, and Kikuchi, T: "Caveolin-3 deficiency causes muscle degeneration in mice."Human Molecular Genetics.. Vol. 9 (20). 3047-3054 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yoshida, M., Hama, H., Ishikawa-Sakurai, M., Imamura, M., Mizuno, Y., Araishi, K., Wakabayashi-Takai, E., Noguchi, S., Sasaoka, T.and Ozawa E.: "Biochemical evidence for association of dystrobrevin with the sarcoglycan-sarcospan complex as abasis for understanding sarcoglycanopathy."Human Molecular. Genetics. Vol. 9 (7). 1033-1040 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Wang, Y., Xu, R., Sasaoka, T., Tonegawa, S., Kung, M.-P., and Sankoorikal, E-B: "Dopamine D2Long receptor-deficient mice display hypolocomotion and reduced level of haloperidolinduced catalepsy."Journal of Neuroscience. Vol. 20 (22). 8305-8314 (2000)
  • Description: 「研究成果報告書概要(欧文)」より