Concentrations of signal transduction proteins mediating adaptation to exercise in fast, slow and electrically stimulated rat muscles

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University of Cambridge (2004) J Physiol 555P, C147

Communications: Concentrations of signal transduction proteins mediating adaptation to exercise in fast, slow and electrically stimulated rat muscles

P. J. Atherton*‡, H. Sutherland†, J. Jarvis†, S. Salmons†, J. Singh‡ and H. Wackerhage*

*Division of Molecular Physiology, School of Life Sciences, WTB/MSI, University of Dundee, DD1 4HN, †Muscle Research Group, Department of Human Anatomy and Cell Biology, University of Liverpool, L69 3GE and. ‡Department of Biological Sciences, University of Central Lancashire, Preston PR1 2HE, UK

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The output of a signal transduction pathway depends both on the strength of the input signal and the signal amplification by the pathway. The amplification, in turn, depends largely on the signalling protein concentrations within a pathway and their control coefficients, to use the metabolic control analysis terminology. The aim was to investigate a) whether signal transduction protein levels differ with a muscle’s phenotype and b) whether the levels in fast muscle respond to chronic electrical stimulation.

Signalling proteins that have previously been shown to regulate phenotype (calcineurin; extracellular signal regulated kinase, ERK1/2), mitochondrial biogenesis (AMP-activated kinase, AMPK; p38 kinase, p38), translation (protein kinase B, PKB; glycogen synthase kinase, GSK3beta; 4E-binding protein, 4E-BP1; p70 S6kinase, p70 S6k), myostatin growth regulation (SMAD2/3) and cachexia (nuclear factor kappaB, NF-kappaB) were measured in rat soleus (Sol; 84 % I fibres), extensor digitorum longus (EDL; 3 % I fibres) and EDL electrically stimulated for 6 weeks at 10 Hz (n = 4 per muscle). For stimulation, miniature stimulators were implanted into the peritoneal cavity under isoflurane/nitrous oxide anaesthesia with their integral electrodes placed close to the common peroneal nerve. Intramuscular buprenorphine (0.1-0.5 mg/kg) was used to provide post-operative analgesia. Rat EDL muscles were chronically stimulated at 10 Hz for 6 weeks. Animals were humanely killed and protein levels were determined by densitometry of Western blots.

The levels of most of the signal transduction proteins differed consistently between slow soleus and fast EDL. Chronic electrical stimulation of EDL also produced repeatable changes in the level of these proteins. The levels of signal transduction proteins involved in phenotype regulation (ERK1/2, calcineurin) or mitochondrial biogenesis (AMPK, p38) differed but there was no obvious relation to phenotype or mitochondrial content. Proteins mediating translation were all higher in EDL than soleus with the exception of the inhibitory GSK3beta, suggesting higher growth signal sensitivity in EDL. This greater sensitivity could be a partial explanation for the greater size of fast type II fibres compared to type I fibres. Chronic electrical stimulation led to a concentration change in fast-to-slow direction with the exception of PKB and GSK3beta, which also mediate insulin-regulated carbohydrate metabolism. The increase in PKB and decrease in GSK3beta in response to stimulation could be a contributory factor to the increased insulin-mediated glucose uptake in response to exercise observed in trained muscle (James et al. 1973). Both myostatin-activated SMAD2/3 and pro-inflammatory-cytokine activated NF-kappaB have been shown to promote muscle loss and cachexia. These proteins are expressed at higher levels in soleus and stimulated muscle suggesting that these muscles display a higher sensitivity to growth-inhibitory stimuli.

Where applicable, experiments conform with Society ethical requirements.

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