Abstract
Studies in murine cell lines and in mouse models suggest that IL-15 promotes myogenesis and may protect against the inflammation-mediated skeletal muscle atrophy which occurs in sarcopenia and cachexia. The effects of IL-15 on human skeletal muscle growth and development remain largely uncharacterised. Myogenic cultures were isolated from the skeletal muscle of young and elderly subjects. Myoblasts were differentiated for 8 d, with or without the addition of recombinant cytokines (rIL-15, rTNFα) and an IL-15 receptor neutralising antibody. Although myotubes were 19% thinner in cultures derived from elderly subjects, rIL-15 increased the thickness of myotubes (MTT) from both age groups to a similar extent. Neutralisation of the high-affinity IL-15 receptor binding subunit, IL-15rα in elderly myotubes confirmed that autocrine concentrations of IL-15 also support myogenesis. Co-incubation of differentiating myoblasts with rIL-15 and rTNFα, limited the reduction in MTT and nuclear fusion index (NFI) associated with rTNFα stimulation alone. IL-15rα neutralisation and rTNFα decreased MTT and NFI further. This, coupled with our observation that myotubes secrete IL-15 in response to TNFα stimulation supports the notion that IL-15 serves to mitigate inflammatory skeletal muscle loss. IL-15 may be an effective therapeutic target for the attenuation of inflammation-mediated skeletal muscle atrophy.
Highlights
Loss of skeletal muscle mass with age, injury and illness is a major contributor to frailty and disability in the elderly[1,2]
To examine the effect of IL-15 on human myotube development, myoblasts from young subjects were differentiated for 8 d in the presence of recombinant human IL-15 at 1, 25 and 100 ng/mL
Given our findings that IL-15 acts to facilitate myotube development in an inflammatory environment and that TNFα induces its secretion from primary human myotubes, we investigated whether disruption of IL15 binding to its receptor would cause a further deterioration in myogenesis in the presence of TNFα
Summary
Loss of skeletal muscle mass with age (sarcopenia), injury and illness is a major contributor to frailty and disability in the elderly[1,2]. Stimulation of myoblasts with rIL-15 (25 ng/mL) induced a small (1.3-fold) but highly significant (p < 0.0001) increase in the expression of myomaker, a cell membrane protein that is essential for myoblast fusion (Fig. 1e).
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