Incidence and severity of myofiber branching with regeneration and aging

Abstract

BackgroundMyofibers with an abnormal branching cytoarchitecture are commonly found in muscular dystrophy and in regenerated or aged nondystrophic muscles. Such branched myofibers from dystrophic mice are more susceptible to damage than unbranched myofibers in vitro, suggesting that muscles containing a high percentage of these myofibers are more prone to injury. Little is known about the regulation of myofiber branching.MethodsTo gain insights into the formation and fate of branched myofibers, we performed in-depth analyses of single myofibers isolated from dystrophic and nondystrophic (myotoxin-injured or aged) mouse muscles. The proportion of branched myofibers, the number of branches per myofiber and the morphology of the branches were assessed.ResultsAged dystrophic mice exhibited the most severe myofiber branching as defined by the incidence of branched myofibers and the number of branches per myofiber, followed by myotoxin-injured, wild-type muscles and then aged wild-type muscles. In addition, the morphology of the branched myofibers differed among the various models. In response to either induced or ongoing muscle degeneration, branching was restricted to regenerated myofibers containing central nuclei. In myotoxin-injured muscles, the amount of branched myofibers remained stable over time.ConclusionWe suggest that myofiber branching is a consequence of myofiber remodeling during muscle regeneration. Our present study lays valuable groundwork for identifying the molecular pathways leading to myofiber branching in dystrophy, trauma and aging. Decreasing myofiber branching in dystrophic patients may improve muscle resistance to mechanical stress.

Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice

“…Such a phenomenon is associated with myofiber branching 43 that results in the typical dystrophic pseudohypertrophy. Branched myofibers are weaker and more susceptible to damage than unbranched fibers, and once formed they do not fuse with parent myofibers 44, 45. Hence, a possible explanation for the lack of muscle hypertrophy is that myostatin knockdown is only effective in wild-type-like myofibers and may be insufficient in rescuing branched myofibers.…”

The Need for a Consensus on the Locution “Central Nuclei” in Striated Muscle Myopathies

“…More recently, users of the “central nuclei” option include renowned researchers in the muscle field in several continents, including North America, Australia, and Europe (McGeachie and Grounds, 1999; McClung et al, 2006; Zampieri et al, 2010a; Pichavant and Pavlath, 2014). Anecdotally speaking, it seems that “centrally located nuclei” is favored by non-English speaker groups, mostly scattered through Europe or East Asia, even though “central nuclei” remains prevalent (Musarò et al, 2007; Coletti et al, 2013; Ikutomo et al, 2014).…”

Effects of loaded voluntary wheel exercise on performance and muscle hypertrophy in young and old male C57Bl/6J mice

“…An increase in branched myofibers with central myonuclei is well documented after myonecrosis and regeneration (either because of experimental injury or endogenous damage in dystrophic muscle; Ontell, 1986;Faber et al, 2014;Pichavant & Pavlath, 2014). In ageing muscle (20-21 months), branched/split myofibers are also evident and a recent study in isolated myofibers demonstrates that they occur without evidence of regeneration, indicating a different and unknown mechanism for this phenomenon (Pichavant & Pavlath, 2014). Another pathology that is widely reported only in ageing male mouse muscles is the accumulation of tubular aggregates: while these increase in male muscles from 6 months of age they were not seen in any muscles of female mice examined up to 19 (Agbulut et al, 2000;Nishikawa et al, 2000;Chevessier et al, 2004) or even at 24 months of age (Kuncl et al, 1989).…”