Driving an Oxidative Phenotype Protects Myh4 Null Mice From Myofiber Loss During Postnatal Growth

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dc.contributor.authorZeng, Caiyunen
dc.contributor.authorShi, Haoen
dc.contributor.authorKirkpatrick, Laila T.en
dc.contributor.authorRicome, Aymericen
dc.contributor.authorPark, Sungkwonen
dc.contributor.authorScheffler, Jason M.en
dc.contributor.authorHannon, Kevin M.en
dc.contributor.authorGrant, Alan L.en
dc.contributor.authorGerrard, David E.en
dc.date.accessioned2022-07-22T16:58:41Zen
dc.date.available2022-07-22T16:58:41Zen
dc.date.issued2022-02-24en
dc.description.abstractPostnatal muscle growth is accompanied by increases in fast fiber type compositions and hypertrophy, raising the possibility that a slow to fast transition may be partially requisite for increases in muscle mass. To test this hypothesis, we ablated the Myh4 gene, and thus myosin heavy chain IIB protein and corresponding fibers in mice, and examined its consequences on postnatal muscle growth. Wild-type and Myh4(-/-) mice had the same number of muscle fibers at 2 weeks postnatal. However, the gastrocnemius muscle lost up to 50% of its fibers between 2 and 4 weeks of age, though stabilizing thereafter. To compensate for the lack of functional IIB fibers, type I, IIA, and IIX(D) fibers increased in prevalence and size. To address whether slowing the slow-to-fast fiber transition process would rescue fiber loss in Myh4(-/-) mice, we stimulated the oxidative program in muscle of Myh4(-/-) mice either by overexpression of PGC-1 alpha, a well-established model for fast-to-slow fiber transition, or by feeding mice AICAR, a potent AMP kinase agonist. Forcing an oxidative metabolism in muscle only partially protected the gastrocnemius muscle from loss of fibers in Myh4(-/-) mice. To explore whether traditional means of stimulating muscle hypertrophy could overcome the muscling deficits in postnatal Myh4(-/-) mice, myostatin null mice were bred with Myh4(-/-) mice, or Myh4(-/-) mice were fed the growth promotant clenbuterol. Interestingly, both genetic and pharmacological stimulations had little impact on mice lacking a functional Myh4 gene suggesting that the existing muscle fibers have maximized its capacity to enlarge to compensate for the lack of its neighboring IIB fibers. Curiously, however, cell signaling events responsible for IIB fiber formation remained intact in the tissue. These findings further show disrupting the slow-to-fast transition of muscle fibers compromises muscle growth postnatally and suggest that type IIB myosin heavy chain expression and its corresponding fiber type may be necessary for fiber maintenance, transition and hypertrophy in mice. The fact that forcing muscle metabolism toward a more oxidative phenotype can partially compensates for the lack of an intact Myh4 gene provides new avenues for attenuating the loss of fast-twitch fibers in aged or diseased muscles.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fphys.2021.785151en
dc.identifier.eissn1664-042Xen
dc.identifier.other785151en
dc.identifier.pmid35283757en
dc.identifier.urihttp://hdl.handle.net/10919/111322en
dc.identifier.volume12en
dc.language.isoenen
dc.publisherFrontiersen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectmyosin heavy chainen
dc.subjectclenbuterolen
dc.subjectoxidative metabolismen
dc.subjectmuscle fiber typeen
dc.subjectPGC-1 alphaen
dc.subjectmyostatinen
dc.subjectclenbuterol (CB)en
dc.titleDriving an Oxidative Phenotype Protects Myh4 Null Mice From Myofiber Loss During Postnatal Growthen
dc.title.serialFrontiers in Physiologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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