Abstract
Chronic, low-level elevation of circulating interleukin (IL)-6 is observed in disease states as well as in many outwardly healthy elderly individuals. Increased plasma IL-6 is also observed after intense, prolonged exercise. In the context of skeletal muscle, IL-6 has variously been reported to regulate carbohydrate and lipid metabolism, increase satellite cell proliferation, or cause muscle wasting. In the present study, we used a rodent local infusion model to deliver modest levels of IL-6, comparable to that present after exercise or with chronic low-level inflammation in the elderly, directly into a single target muscle in vivo. The aim of this study was to examine the direct effects of IL-6 on skeletal muscle in the absence of systemic changes in this cytokine. Data included cellular and molecular markers of cytokine and growth factor signaling (phosphorylation and mRNA content) as well as measurements to detect muscle atrophy. IL-6 infusion resulted in muscle atrophy characterized by a preferential loss of myofibrillar protein (-17%). IL-6 induced a decrease in the phosphorylation of ribosomal S6 kinase (-60%) and STAT5 (-33%), whereas that of STAT3 was increased approximately twofold. The changes seen in the IL-6-infused muscles suggest alterations in the balance of growth factor-related signaling in favor of a more catabolic profile. This suggests that downregulation of growth factor-mediated intracellular signaling may be a mechanism contributing to the development of muscle atrophy induced by elevated IL-6.
Highlights
We recently reported that locally elevated levels of growth hormone (GH) can stimulate the development of skeletal muscle hypertrophy in vivo and that this response is most likely mediated by insulin-like growth factor (IGF)-I [3]
The fact that elevated IL-6 can be a feature of such a wide variety of conditions, including disease, aging, and participation in intense exercise, indicates that a clear understanding of the direct effects of this cytokine on muscle is of utmost importance
This is the first study to examine the effects of a relatively modest dose of IL-6 on skeletal muscle in the absence of somatic level alterations that would be expected to occur with systemic elevation of this cytokine
Summary
IL-6 has been shown to participate in metabolic control pathways during exercise [20, 43, 48, 49] These roles appear to be at variance with the traditional view of IL-6 as a catabolic agent in skeletal muscle. With regard to compensatory muscle adaptation, autocrine/paracrine IGF-I has been shown to regulate aspects of the compensatory adaptation of skeletal muscle as well as muscle growth and development We recently reported that locally (e.g., within a single muscle) elevated levels of GH can stimulate the development of skeletal muscle hypertrophy in vivo and that this response is most likely mediated by IGF-I [3]
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