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Journal of Physiology (2001), 535.1, pp. 1-1
© Copyright 2001 The Physiological Society
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At a meeting some years ago I saw Professor Sam Perry of Birmingham University, one of the pioneers of British muscle biochemistry, present a slide juxtaposing two brothers who were identical twins. One had gone in for body-building and the other had decided to become a distance runner. The point was, of course, that despite having identical genomes, these men had managed to sculpt their bodies in completely different ways by training. The plasticity of muscle has long been recognised but apart from some biologically trivial generalisations (resistance exercise causing an increase in muscle bulk and repeated moderate dynamic exercise causing an increase in muscle oxidative capacity) we have made slow progress in understanding the mechanisms involved. Most of our information is about the distal processes involved (e.g. selective hypertrophy of particular fibres, alterations in mitochondrial density and changes in myosin heavy chain phenotypes). Some of the changes appear to be almost immediate, for example the changes in the rate of translation of mRNA for muscle proteins, which falls during exercise and rebounds during recovery (Rennie & Tipton, 2000). Others take days to months and involve changes in gene expression, both of the type and the amount of particular proteins such as myosin subtypes or cytochrome C (Pette, 2000). The difficult question to answer is, what is the nature of the proximal processes that act, both acutely and chronically, to link the pattern of contractile activity with the cellular changes, allowing adaptation to new circumstances? There have been many conjectures in the past involving alterations in such things as ATP/ADP concentration ratios, availability of free creatine, the redox state of muscle, its pH, etc. There has also been speculation based upon the degree of tension experienced by muscle membranes and the intracellular cytoskeletal system and their connections with the extracellular matrix and other muscle cells through, for example, integrins. It is relatively trivial to conceive of a scheme which involves alterations in transcription and translation as a result of force signals due to contractile activity being transmitted, for example, to the muscle membrane and to integrin anchors and thereby retransmitted to the interior of muscles via membrane-associated sensor and signalling elements, these signals being modulated by cross-talk with metabolic signals. However, such a model still has to account for the two major modes of response, i.e. hypertrophy and increases in oxidative capacity, and how, under certain circumstances, these can even be combined (e.g. in well-trained distance runners type 1 fibres are not only more oxidative but they are bigger than in untrained individuals).
Physiologists interested in these questions have, over the past few years, started to investigate the relevance of the mitogen-activated protein (MAP) kinases which appear to be involved in maintenance, growth and adaptation in many cell types. Different branches of the MAP kinase family appear to have different roles in control of cellular responsiveness. Factors as disparate as oxygen free radicals, hydrogen ions, mechanical stress as well as, of course, hormones, growth factors and mitogens specifically activate some kinase pathways and not others. Crucially, MAP kinase activation can result not only in the production of transcription factors mediating gene expression but, on a much shorter time scale, can stimulate the activity of the translational stage of protein synthesis through eukaryotic initiation and elongation factors.
In a paper published in this issue of The Journal of Physiology, Wretman and her colleagues from the Karolinska Institute have, elegantly and imaginatively, used the mechanical, contractile and metabolic properties of muscle in order to unravel the involvement of three MAP kinases, the extracellular signal-regulated kinases 1 and 2 (MAPKerk1/2) and the stress-activated protein kinase p38 (MAPKp38). For example, mild passive stretch can increase the tension in muscle membranes without causing metabolic alterations; however, both shortening and lengthening active contractions of muscle (so-called concentric and eccentric contraction) lead to metabolic activity. Also the strain generated is greater and of a different type for eccentric rather than concentric contractions, whereas the metabolic disturbances and proton production are greater for concentric contraction. The Karolinska team found that concentric contraction of rat muscle in situ induced dramatic increases in MAPKerk1/2 activity whereas mild, passive stretch caused only moderate elevations. Antioxidants and free radical scavengers (which mop up reactive oxygen species) diminished the responses and acidity increased them. These manoeuvres had no effect on MAPKp38 whereas severe passive stretch or eccentric contractions, which place great strain on the muscle, but with little metabolic disturbance, markedly increased the MAPKp38 activity. The authors have come up with a hypothesis which may explain the links between different types of contractile activity and the cellular responses of muscle (Fig. 1). They speculate that MAPKerk1/2, which is activated chiefly by metabolic events (including acidification), is more likely to be involved in modulating muscle's oxidative capacity, whereas activation of MAPKp38 via the production of high levels of mechanical stress is more likely to be involved in the adaptive changes resulting in hypertrophy of muscle. These findings, although raising as many questions as they answer, are not only intrinsically interesting but are a good example of how modern cell and molecular biochemistry can be harnessed to help explain adaptations which are expressed at the systemic, physiological level. Furthermore, they hold open the possibility of pharmacological intervention, which could be particularly valuable in maintaining muscle mass during ageing or reversing muscle wasting during critical illness.
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Figure 1 Possible scheme of involvement of MAP kinases and signalling of different modes of muscle activity to adaptive processes. | ||
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REFERENCES |
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| PETTE D. (2001). Journal of Applied Physiology 90, 1119-1124 | [Abstract/Full Text] |
| RENNIE M. J. & TIPTON, K. D. (2000). Annual Review of Nutrition 2, 459-485 | |
| WRETMAN C. et al. (2001). Journal of Physiology 535, 155-164 | [Abstract/Full Text] |
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