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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online April 1, 2004 as doi:10.1096/fj.03-1259fje. |
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* Skeletal Muscle Research Laboratory, Centre for Nutrition, Metabolism & Endocrinology; and
Microvascular Research Group, School of Medical Sciences, RMIT University, Melbourne, Australia
2 Correspondence: Skeletal Muscle Research Laboratory, Centre for Nutrition, Metabolism & Endocrinology, RMIT University, PO Box 71, Bundoora 3083, Victoria, Australia. E-mail: natalie.hiscock{at}rmit.edu.au
SPECIFIC AIMS
It is now well established that acute skeletal muscle contraction causes an elevation in the circulating concentration of cytokine interleukin-6 (IL-6) that can be attributed to a rapid rate of gene transcription within skeletal muscle biopsy specimens and translation of IL-6 protein that is released from contracting skeletal muscle. Although it was recently shown that muscle contraction induced an increase in IL-6 protein within muscle fibers, it is not yet clear that IL-6 is produced within these fibers and not trafficked into cells to perform intracellular roles. This investigation aimed to determine whether muscle cells per se are the source of contraction-induced elevation in IL-6 in human skeletal muscle, and to characterize distribution of IL-6 within and between fibers. IL-6 protein and mRNA expression within sectioned muscle biopsy tissue (collected before and after contraction) was analyze; each fiber type was characterized and the glycogen content of each fiber was assessed. Simultaneous examination of IL-6 gene cellular localization and protein within fiber cross sections enabled this study to categorically determine whether muscle cells are a source of IL-6 during contraction.
PRINCIPAL FINDINGS
1. IL-6 protein is elevated after contraction in predominantly type 2 muscle fibers
IL-6 protein was elevated in muscle biopsy cross-sectional tissue from precontraction (PRE) to postcontraction (POST) (P<0.05) and could clearly be observed both within and between muscle fibers (Fig. 1
). At PRE, IL-6 protein was uniformly expressed across muscle fibers at low levels. At POST, IL-6 protein was expressed in a fiber-specific manner. Distribution of IL-6 protein was then examined by quantitatively comparing muscle fibers with low glycogen content (type 1 fibers) and fibers with high glycogen content (type 2 fibers) at POST. This analysis revealed that IL-6 protein was expressed predominantly in type 2 muscle fibers with HIGH glycogen content (P<0.05).
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2. IL-6 mRNA is elevated after contraction in predominantly type 2 muscle fibers
IL-6 mRNA as measured by real time RT-PCR was increased (P<0.05) 18 ± 8-fold when comparing PRE with POST. As can be seen in Fig. 2
, this coincided with an increase in IL-6 mRNA in skeletal muscle fibers comparing PRE with POST contraction. At PRE, IL-6 mRNA was expressed peripherally at low levels in all fibers and there was a virtual absence of IL-6 in the center of the myocytes. However, at POST, IL-6 mRNA was selectively expressed throughout some, but not all fibers (Fig. 2)
. Further examination of these fibers showed that type 2 fibers were expressing IL-6 mRNA at a much greater level than type 1 fibers and these fibers also had greater glycogen content.
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CONCLUSIONS AND SIGNIFICANCE
Our data clearly demonstrate that human skeletal myocytes are a source of contraction-induced IL-6 (Fig. 3
). We provide solid evidence that IL-6 is predominantly produced by type 2 fibers. We suggest that augmented increase in IL-6 protein release and mRNA content during prior glycogen depletion shown previously is due to earlier depletion of type 1 fibers, resulting in earlier recruitment of type 2 fibers. Based on the recent hypothesis that an increase in contraction-induced cytosolic Ca2+ levels may be one factor regulating IL-6 production, and the fact that action potential- stimulated total Ca2+ release and rate of release are 3-fold greater in type 2 fibers, we propose that localization of IL-6 to type 2 fibers may occur via a Ca2+-dependent pathway.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-1259fje; 
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