Sci. Signal., 12 August 2008
Physiology The Benefits of Exercise Without the Sweat
Nancy R. Gough
Science Signaling, AAAS, Washington, DC 20005, USA
Skeletal muscle is one of the many organs that exhibit adaptations in response to exercise. Skeletal muscle undergoes a transcriptional reprogramming to increase mitochondrial biogenesis and oxidative phosphorylation, fatty acid oxidation, and slow-twitch contractile proteins, which not only contribute to enhanced performance and endurance but also contribute to protection from obesity and metabolic disorders. Overexpression of an activated form of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) in the skeletal muscles of mice appears to preprogram muscle fibers to an oxidative phenotype and increases running endurance in untrained mice. Treatment of adult mice with the PPAR agonist GW1516 in combination with exercise increases endurance and reprograms skeletal muscle. Narkar et al. show that GW1516 does not increase endurance in the absence of exercise and that both are necessary to increase the proportion of slow-twitch muscle, increase mitochondrial biogenesis, and increase the transcription of genes involved in fatty acid storage and uptake. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is constitutively activated in the muscles of the transgenic mice overexpressing activated PPAR. Treatment of mice with AICAR, an AMPK agonist, increased their endurance in the absence of any training. AMPK activation with AICAR combined with PPAR activation with GW1516 in sedentary mice produced a transcriptional profile that was unique (189 genes), but 52 of these overlapped with many of the genes regulated by exercise combined with activation of PPAR with GW1516 (130 genes). Primary muscle cultures from wild-type or PPAR-null mice revealed that the effects of GW1516 and AICAR on gene expression required PPAR. Transfected AD293 cells revealed that the subunits of AMPK coimmunoprecipitated with PPAR but did not appear to phosphorylate PPAR. Thus, AMPK may promote PPAR activity either through a protein-protein interaction or by phosphorylating coactivators. Although the ability of a single drug to mimic the effects of exercise in skeletal muscle in mice is tantalizing, it remains to be determined whether these results can be extrapolated to humans and what effects activation of AMPK may have on other organs that are important for mediating the health benefits of exercise (see Richter et al.).
V. A. Narkar, M. Downes, R. T. Yu, E. Embler, Y.-X. Wang, E. Banayo, M. M. Mihaylova, M. C. Nelson, Y. Zou, H. Juguilon, H. Kang, R. J. Shaw, R. M. Evans, AMPK and PPAR agonists are exercise mimetics. Cell 134, 405-415 (2008). [PubMed]
E. A. Richter, B. Kiens, J. F. P. Wojtaszewski, Can exercise mimetics substitute for exercise? Cell Metab. 8, 96-98 (2008). [PubMed]
Citation: N. R. Gough, The Benefits of Exercise Without the Sweat. Sci. Signal. 1, ec284 (2008).
The editors suggest the following Related Resources on Science sites:
In Science Signaling
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882