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Perlecan Facilitates Neuronal Nitric Oxide Synthase Delocalization in Denervation-Induced Muscle Atrophy.
Nakada, Satoshi; Yamashita, Yuri; Machida, Shuichi; Miyagoe-Suzuki, Yuko; Arikawa-Hirasawa, Eri.
Affiliation
  • Nakada S; Japanese Center for Research on Women in Sport, Juntendo University Graduate School of Health and Sports Science, Chiba 270-1695, Japan.
  • Yamashita Y; Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
  • Machida S; Japanese Center for Research on Women in Sport, Juntendo University Graduate School of Health and Sports Science, Chiba 270-1695, Japan.
  • Miyagoe-Suzuki Y; Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
  • Arikawa-Hirasawa E; Japanese Center for Research on Women in Sport, Juntendo University Graduate School of Health and Sports Science, Chiba 270-1695, Japan.
Cells ; 9(11)2020 11 23.
Article in En | MEDLINE | ID: mdl-33238404
Perlecan is an extracellular matrix molecule anchored to the sarcolemma by a dystrophin-glycoprotein complex. Perlecan-deficient mice are tolerant to muscle atrophy, suggesting that perlecan negatively regulates mechanical stress-dependent skeletal muscle mass. Delocalization of neuronal nitric oxide synthase (nNOS) from the sarcolemma to the cytosol triggers protein degradation, thereby initiating skeletal muscle atrophy. We hypothesized that perlecan regulates nNOS delocalization and activates protein degradation during this process. To determine the role of perlecan in nNOS-mediated mechanotransduction, we used sciatic nerve transection as a denervation model of gastrocnemius muscles. Gastrocnemius muscle atrophy was significantly lower in perinatal lethality-rescued perlecan-knockout (Hspg2-/--Tg) mice than controls (WT-Tg) on days 4 and 14 following surgery. Immunofluorescence microscopy showed that cell membrane nNOS expression was reduced by denervation in WT-Tg mice, with marginal effects in Hspg2-/--Tg mice. Moreover, levels of atrophy-related proteins-i.e., FoxO1a, FoxO3a, atrogin-1, and Lys48-polyubiquitinated proteins-increased in the denervated muscles of WT-Tg mice but not in Hspg2-/--Tg mice. These findings suggest that during denervation, perlecan promotes nNOS delocalization from the membrane and stimulates protein degradation and muscle atrophy by activating FoxO signaling and the ubiquitin-proteasome system.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Muscular Atrophy / Heparan Sulfate Proteoglycans / Nitric Oxide Synthase Type I Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Cells Year: 2020 Document type: Article Affiliation country: Japan Country of publication: Switzerland

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Muscular Atrophy / Heparan Sulfate Proteoglycans / Nitric Oxide Synthase Type I Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Cells Year: 2020 Document type: Article Affiliation country: Japan Country of publication: Switzerland