Abstract
Postnatal 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-1α, 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.
Highlights
IIX fibers in Myh4−/− muscle decreased, though type I and IIA fibers increased in size (Figure 6D). These findings show clenbuterol cannot elicit a hypertrophic effect in mice lacking a functional Myh4 gene compared to their wild-type counterparts and suggest the added lean growth accretion caused by betaadrenergic agonist feeding may be requisite on changes in muscle fiber types, especially including type IIB fibers
We found (1) muscle fiber number remains unchanged until after birth, when IIB fibers progressively decreases between week 2 and 4; (2) muscle compensates for the loss of IIB fibers by increasing the proportion of type I and IIA fibers, and most notably, IIX fibers; (3) driving muscle metabolism from glycolytic to oxidative, either by genetically over-expressing PGC-1α or pharmaceutically by AICAR, partially rescues this loss in muscle mass and fiber number in Myh4−/− muscle; (4) stimulating muscle growth in mice lacking Myh4 either pharmacologically or through genetic approaches fails to rescue muscle mass and fiber number; and (5) those signal pathways driving fast-twitch program and IIB fiber formation remains intact in Myh4−/− muscle
This finding indicates that after birth, fetal muscle fiber types in mouse muscle are quickly replaced by more glycolytic, fast-twitch fibers to satisfy the needs for greater contractile power and speed
Summary
Skeletal muscle consists of a diverse set of muscle cells that can be classified by the relative expression of major sarcomere myosin heavy chain (MyHC) isoforms (Schiaffino and Reggiani, 1994; Weiss and Leinwand, 1996; Pette and Staron, 2000), whose ATPase activity is reflective of the contractile speed of the muscle fiber and correlates with the fiber’s metabolic profile (Schiaffino and Reggiani, 1994; Pette and Staron, 2000; Spangenburg and Booth, 2003; Bourdeau Julien et al, 2018). Most muscle fibers consist homogeneously of either type of MyHC I, IIA, IIX(D) or IIB isoforms, encoded by Myh, Myh, Myh, and Myh, respectively. Neuronal activity drives fiber type specification, metabolite-dependent signaling, such as AMPK and mTORC1, and transcription factors, such as PPAR and PGC-1α, help fine tune fiber type specification (Bourdeau Julien et al, 2018). Other studies show that nutrients can promote slow fiber program via AMPK signaling (Wen et al, 2020; Xu et al, 2020a,b)
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