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Beta3-integrin mediates satellite cell differentiation in regenerating mouse muscle.

ABSTRACT: Skeletal muscle satellite cells can sense various forms of environmental cues and initiate coordinated signaling that activates myogenesis. Although this process involves cellular membrane receptor integrins, the role of integrins in myogenesis is not well defined. Here, we report a regulatory role of ?3-integrin, which was previously thought not expressed in muscle, in the initiation of satellite cell differentiation. Undetected in normal muscle, ?3-integrin expression in mouse hindlimb muscles is induced dramatically from 1 to 3 d after injury by cardiotoxin. The source of ?3-integrin expression is found to be activated satellite cells. Proliferating C2C12 myoblasts also express ?3-integrin, which is further up-regulated transiently on differentiation. Knockdown of ?3-integrin expression attenuates Rac1 activity, impairs myogenic gene expression, and disrupts focal adhesion formation and actin organization, resulting in impaired myoblast migration and myotube formation. Conversely, overexpression of constitutively active Rac1 rescues myotube formation. In addition, a ?3-integrin-neutralizing antibody similarly blocked myotube formation. Comparing with wild-type littermates, myogenic gene expression and muscle regeneration in cardiotoxin-injured ?3-integrin-null mice are impaired, as indicated by depressed expression of myogenic markers and morphological disparities. Thus, ?3-integrin is a mediator of satellite cell differentiation in regenerating muscle.

SUBMITTER: Liu H

PROVIDER: S-EPMC3101029 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Beta3-integrin mediates satellite cell differentiation in regenerating mouse muscle.

Liu Huijie H Niu Airu A Chen Shuen-Ei SE Li Yi-Ping YP

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20110224 6

Skeletal muscle satellite cells can sense various forms of environmental cues and initiate coordinated signaling that activates myogenesis. Although this process involves cellular membrane receptor integrins, the role of integrins in myogenesis is not well defined. Here, we report a regulatory role of β3-integrin, which was previously thought not expressed in muscle, in the initiation of satellite cell differentiation. Undetected in normal muscle, β3-integrin expression in mouse hindlimb muscles ...[more]

PMID: 21350117

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Project description:BackgroundPerturbation in cell adhesion and growth factor signalling in satellite cells results in decreased muscle regenerative capacity. Cdon (also called Cdo) is a component of cell adhesion complexes implicated in myogenic differentiation, but its role in muscle regeneration remains to be determined.MethodsWe generated inducible satellite cell-specific Cdon ablation in mice by utilizing a conditional Cdon allele and Pax7 CreERT2 . To induce Cdon ablation, mice were intraperitoneally injected with tamoxifen (tmx). Using cardiotoxin-induced muscle injury, the effect of Cdon depletion on satellite cell function was examined by histochemistry, immunostaining, and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay. Isolated myofibers or myoblasts were utilized to determine stem cell function and senescence. To determine pathways related to Cdon deletion, injured muscles were subjected to RNA sequencing analysis.ResultsSatellite cell-specific Cdon ablation causes impaired muscle regeneration with fibrosis, likely attributable to decreased proliferation, and senescence, of satellite cells. Cultured Cdon-depleted myofibers exhibited 32 ± 9.6% of EdU-positive satellite cells compared with 58 ± 4.4% satellite cells in control myofibers (P < 0.05). About 32.5 ± 3.7% Cdon-ablated myoblasts were positive for senescence-associated β-galactosidase (SA-β-gal) while only 3.6 ± 0.5% of control satellite cells were positive (P < 0.001). Transcriptome analysis of muscles at post-injury Day 4 revealed alterations in genes related to mitogen-activated protein kinase signalling (P < 8.29 e-5 ) and extracellular matrix (P < 2.65 e-24 ). Consistent with this, Cdon-depleted tibialis anterior muscles had reduced phosphorylated extracellular signal-regulated kinase (p-ERK) protein levels and expression of ERK targets, such as Fos (0.23-fold) and Egr1 (0.31-fold), relative to mock-treated control muscles (P < 0.001). Cdon-depleted myoblasts exhibited impaired ERK activation in response to basic fibroblast growth factor. Cdon ablation resulted in decreased and/or mislocalized integrin β1 activation in satellite cells (weak or mislocalized integrin1 in tmx = 38.7 ± 1.9%, mock = 21.5 ± 6%, P < 0.05), previously linked with reduced fibroblast growth factor (FGF) responsiveness in aged satellite cells. In mechanistic studies, Cdon interacted with and regulated cell surface localization of FGFR1 and FGFR4, likely contributing to FGF responsiveness of satellite cells. Satellite cells from a progeria model, Zmpste24-/- myofibers, showed decreased Cdon levels (Cdon-positive cells in Zmpste24-/- = 63.3 ± 11%, wild type = 90 ± 7.7%, P < 0.05) and integrin β1 activation (weak or mislocalized integrin β1 in Zmpste24-/- = 64 ± 6.9%, wild type = 17.4 ± 5.9%, P < 0.01).ConclusionsCdon deficiency in satellite cells causes impaired proliferation of satellite cells and muscle regeneration via aberrant integrin and FGFR signalling.

Dataset Information

Beta3-integrin mediates satellite cell differentiation in regenerating mouse muscle.

Publications

Beta3-integrin mediates satellite cell differentiation in regenerating mouse muscle.

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