title: Myogenic differentiation during regrowth of atrophied skeletal muscle is associated with inactivation of GSK-3beta.
abstract: Muscle atrophy contributes to morbidity and mortality in aging and chronic disease, emphasizing the need to gain understanding of the mechanisms involved in muscle atrophy and (re)growth. We hypothesized that the magnitude of muscle regrowth during recovery from atrophy determines whether myonuclear accretion and myogenic differentiation are required and that insulin-like growth factor (IGF)-I/Akt/glycogen synthase kinase (GSK)-3beta signaling differs between regrowth responses. To address this hypothesis we subjected mice to hindlimb suspension (HS) to induce atrophy of soleus (-40%) and plantaris (-27%) muscle. Reloading-induced muscle regrowth was complete after 14 days and involved an increase in IGF-IEa mRNA expression that coincided with Akt phosphorylation in both muscles. In contrast, phosphorylation and inactivation of GSK-3beta were observed during soleus regrowth only. Furthermore, soleus but not plantaris regrowth involved muscle regeneration based on a transient increase in expression of histone 3.2 and myosin heavy chain-perinatal, which are markers of myoblast proliferation and differentiation, and a strong induction of muscle regulatory factor (MRF) expression. Experiments in cultured muscle cells showed that IGF-I-induced MRF expression is facilitated by inactivation of GSK-3beta and selectively occurs in the myoblast population. This study suggests that induction of IGF-I expression and Akt phosphorylation during recovery from muscle atrophy is independent of the magnitude of muscle regrowth. Moreover, our data demonstrate for the first time that the regenerative response characterized by myoblast proliferation, differentiation, and increased MRF expression in recovering muscle is associated with the magnitude of regrowth and may be regulated by inactivation of GSK-3beta.
authors.affiliation: Department of Respiratory Medicine, Maastricht University PO Box 5800, 6202 AZ Maastricht, The Netherlands.
authors.forename: Jos L J
authors.initials: JL
authors.lastname: van der Velden
authors.forename: Ramon C J
authors.initials: RC
authors.lastname: Langen
authors.forename: Marco C J M
authors.initials: MC
authors.lastname: Kelders
authors.forename: Jodil
authors.initials: J
authors.lastname: Willems
authors.forename: Emiel F M
authors.initials: EF
authors.lastname: Wouters
authors.forename: Yvonne M W
authors.initials: YM
authors.lastname: Janssen-Heininger
authors.forename: Annemie M W J
authors.initials: AM
authors.lastname: Schols
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D004195:Disease Models, Animal; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D019417:Hindlimb Suspension; D006657:Histones / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D032446:Myoblasts / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012038:Regeneration; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D020717:Eukaryotic Initiation Factor-2B; D006657:Histones; D018006:Myogenic Regulatory Factors; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D018995:Myosin Heavy Chains