title: Perlecan inhibits autophagy to maintain muscle homeostasis in mouse soleus muscle.
abstract: The autophagy-lysosome system is essential for muscle protein synthesis and degradation equilibrium, and its dysfunction has been linked to various muscle disorders. It has been reported that a diverse collection of extracellular matrix constituents, including decorin, collagen VI, laminin α2, endorepellin, and endostatin, can modulate autophagic signaling pathways. However, the association between autophagy and perlecan in muscle homeostasis remains unclear. The mechanical unloading of perlecan-deficient soleus muscles resulted in significantly decreased wet weights and cross-section fiber area compared with those of control mice. We found that perlecan deficiency in slow-twitch soleus muscles enhanced autophagic activity. This was accompanied by a decrease in autophagic substrates, such as p62, and an increase in LC3II levels. Furthermore, perlecan deficiency caused a reduction in the phosphorylation levels of p70S6k and Akt and increased the phosphorylation of AMPKα. Our findings suggested that perlecan inhibits the autophagic process through the activation of the mTORC1 pathway. This autophagic response may be a novel target for enhancing the efficacy of skeletal muscle atrophy treatment.
authors: Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors: Liang
authors: L
authors: Ning
authors: Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors: Zhuo
authors: Z
authors: Xu
authors: Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
authors: Norihiko
authors: N
authors: Furuya
authors: Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors: Risa
authors: R
authors: Nonaka
authors: National Institute of Dental and Craniofacial Research, NIH, Bethesda 90814, USA.
authors: Yoshihiko
authors: Y
authors: Yamada
authors: Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan. Electronic address: ehirasaw@juntendo.ac.jp.
authors: Eri
authors: E
authors: Arikawa-Hirasawa
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000172:deficiency / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D058971:Tenotomy
chemical_list: C447413:Col2a1 protein, mouse; D024043:Collagen Type II; D019812:Heparan Sulfate Proteoglycans; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D011993:Recombinant Fusion Proteins; C071927:perlecan; D049452:Green Fluorescent Proteins; C548179:Prkaa1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: Autophagy; Mechanical stress; Muscle atrophy; Perlecan; Soleus muscle