title: The CHC22 clathrin-GLUT4 transport pathway contributes to skeletal muscle regeneration.
abstract: Mobilization of the GLUT4 glucose transporter from intracellular storage vesicles provides a mechanism for insulin-responsive glucose import into skeletal muscle. In humans, clathrin isoform CHC22 participates in formation of the GLUT4 storage compartment in skeletal muscle and fat. CHC22 function is limited to retrograde endosomal sorting and is restricted in its tissue expression and species distribution compared to the conserved CHC17 isoform that mediates endocytosis and several other membrane traffic pathways. Previously, we noted that CHC22 was expressed at elevated levels in regenerating rat muscle. Here we investigate whether the GLUT4 pathway in which CHC22 participates could play a role in muscle regeneration in humans and we test this possibility using CHC22-transgenic mice, which do not normally express CHC22. We observed that GLUT4 expression is elevated in parallel with that of CHC22 in regenerating skeletal muscle fibers from patients with inflammatory and other myopathies. Regenerating human myofibers displayed concurrent increases in expression of VAMP2, another regulator of GLUT4 transport. Regenerating fibers from wild-type mouse skeletal muscle injected with cardiotoxin also showed increased levels of GLUT4 and VAMP2. We previously demonstrated that transgenic mice expressing CHC22 in their muscle over-sequester GLUT4 and VAMP2 and have defective GLUT4 trafficking leading to diabetic symptoms. In this study, we find that muscle regeneration rates in CHC22 mice were delayed compared to wild-type mice, and myoblasts isolated from these mice did not proliferate in response to glucose. Additionally, CHC22-expressing mouse muscle displayed a fiber type switch from oxidative to glycolytic, similar to that observed in type 2 diabetic patients. These observations implicate the pathway for GLUT4 transport in regeneration of both human and mouse skeletal muscle, and demonstrate a role for this pathway in maintenance of muscle fiber type. Extrapolating these findings, CHC22 and GLUT4 can be considered markers of muscle regeneration in humans.
authors.affiliation: The G.W. Hooper Foundation, Departments of Bioengineering and Therapeutic Sciences, Pharmaceutical Chemistry, and Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America ; Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hoshino
authors.forename: Kazuho
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Stéphane
authors.initials: S
authors.lastname: Vassilopoulos
authors.forename: Stéphane M
authors.initials: SM
authors.lastname: Camus
authors.forename: Christine A
authors.initials: CA
authors.lastname: Griffin
authors.forename: Christopher
authors.initials: C
authors.lastname: Esk
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Torres
authors.forename: Norio
authors.initials: N
authors.lastname: Ohkoshi
authors.forename: Akiko
authors.initials: A
authors.lastname: Ishii
authors.forename: Akira
authors.initials: A
authors.lastname: Tamaoka
authors.forename: Birgit H
authors.initials: BH
authors.lastname: Funke
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
authors.forename: Marta
authors.initials: M
authors.lastname: Margeta
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rando
authors.forename: Frances M
authors.initials: FM
authors.lastname: Brodsky
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002454:Cell Differentiation; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism*; D033922:Clathrin Heavy Chains / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism; D009135:Muscular Diseases / Q000378:metabolism / Q000473:pathology*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D012038:Regeneration / Q000502:physiology*
chemical_list: C101272:CLTCL1 protein, human; D002966:Clathrin; D051275:Glucose Transporter Type 4; D033922:Clathrin Heavy Chains; D005947:Glucose