G.P.117 Clinical implications of the proposal that sarcolemma properties of actively growing myofibres differ to those of mature adult myofibres

Abstract

Abstract The new hypothesise that ‘the sarcolemma of an actively growing myofibre has different properties to the sarcolemma of a mature adult myofibre’ (Grounds & Shavlakadze, 2011, Bioessays) is supported by data showing that elevated IGF-1 triggers a signalling response in growing, but not adult, myofibres. Differences in sarcolemmal properties between growing and adult myofibres are also indicated by the time of clinical onset of various inherited genetic myopathies involving proteins associated with the sarcolemma e.g. Duchenne muscular dystrophy (due to defects in dystrophin) is a paediatric disease and the dystropathology appears to be exacerbated by growth. In striking contrast, young patients with defective dysferlin (another membrane-associated protein) appear to be pre-symptomatic during growth and adolescence and they are often very active in sports, with clinical manifestation usually very shortly after cessation of the main growth phase: thus the reliance on dysferlin seems to be very different between growing and mature adult myofibres. If this hypothesis is true, then the need to use ‘mature muscle’ experimental models (isolated myofibres in culture or adult animals in vivo) for these post-growth myopathies, rather than immature myofibres (e.g. cultured myotubes) is emphasised, in order to define the molecular basis, and identify the best targets for therapies, for dysferlinopathies. During growth, multinucleated myofibres increase enormously in size and volume with dramatic increases in length (up to ∼600 mm): this differs markedly to most mononucleated cells, e.g. fibroblasts, that remain at a relatively small size (∼10–20 μm diameter). In addition, myofibres are long-lived and probably persist throughout the life of an individual (in the absence of severe injury that results in myonecrosis). The consequences of a dynamic expanding sarcolemma during growth, compared with an adult myofibre of a fixed length, have many scientific and clinical implications.