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      Exercise and Health: Can Biotechnology Confer Similar Benefits?


      PLoS Medicine

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          Education and public policies are largely failing to encourage people to exercise. Could our knowledge of exercise biology lead to pharmaceutical treaments that could confer the same benefits as exercise?

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          Most cited references 51

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          Actual causes of death in the United States, 2000.

           Ali Mokdad (2004)
          Modifiable behavioral risk factors are leading causes of mortality in the United States. Quantifying these will provide insight into the effects of recent trends and the implications of missed prevention opportunities. To identify and quantify the leading causes of mortality in the United States. Comprehensive MEDLINE search of English-language articles that identified epidemiological, clinical, and laboratory studies linking risk behaviors and mortality. The search was initially restricted to articles published during or after 1990, but we later included relevant articles published in 1980 to December 31, 2002. Prevalence and relative risk were identified during the literature search. We used 2000 mortality data reported to the Centers for Disease Control and Prevention to identify the causes and number of deaths. The estimates of cause of death were computed by multiplying estimates of the cause-attributable fraction of preventable deaths with the total mortality data. Actual causes of death. The leading causes of death in 2000 were tobacco (435 000 deaths; 18.1% of total US deaths), poor diet and physical inactivity (365 000 deaths; 15.2%) [corrected], and alcohol consumption (85 000 deaths; 3.5%). Other actual causes of death were microbial agents (75 000), toxic agents (55 000), motor vehicle crashes (43 000), incidents involving firearms (29 000), sexual behaviors (20 000), and illicit use of drugs (17 000). These analyses show that smoking remains the leading cause of mortality. However, poor diet and physical inactivity may soon overtake tobacco as the leading cause of death. These findings, along with escalating health care costs and aging population, argue persuasively that the need to establish a more preventive orientation in the US health care and public health systems has become more urgent.
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            Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres.

            The biochemical basis for the regulation of fibre-type determination in skeletal muscle is not well understood. In addition to the expression of particular myofibrillar proteins, type I (slow-twitch) fibres are much higher in mitochondrial content and are more dependent on oxidative metabolism than type II (fast-twitch) fibres. We have previously identified a transcriptional co-activator, peroxisome-proliferator-activated receptor-gamma co-activator-1 (PGC-1 alpha), which is expressed in several tissues including brown fat and skeletal muscle, and that activates mitochondrial biogenesis and oxidative metabolism. We show here that PGC-1 alpha is expressed preferentially in muscle enriched in type I fibres. When PGC-1 alpha is expressed at physiological levels in transgenic mice driven by a muscle creatine kinase (MCK) promoter, a fibre type conversion is observed: muscles normally rich in type II fibres are redder and activate genes of mitochondrial oxidative metabolism. Notably, putative type II muscles from PGC-1 alpha transgenic mice also express proteins characteristic of type I fibres, such as troponin I (slow) and myoglobin, and show a much greater resistance to electrically stimulated fatigue. Using fibre-type-specific promoters, we show in cultured muscle cells that PGC-1 alpha activates transcription in cooperation with Mef2 proteins and serves as a target for calcineurin signalling, which has been implicated in slow fibre gene expression. These data indicate that PGC-1 alpha is a principal factor regulating muscle fibre type determination.
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              The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors.

              Skeletal muscle size depends upon a dynamic balance between anabolic (or hypertrophic) and catabolic (or atrophic) processes. Previously, no link between the molecular mediators of atrophy and hypertrophy had been reported. We demonstrate a hierarchy between the signals which mediate hypertrophy and those which mediate atrophy: the IGF-1/PI3K/Akt pathway, which has been shown to induce hypertrophy, prevents induction of requisite atrophy mediators, namely the muscle-specific ubiquitin ligases MAFbx and MuRF1. Moreover, the mechanism for this inhibition involves Akt-mediated inhibition of the FoxO family of transcription factors; a mutant form of FOXO1, which prevents Akt phosphorylation, thereby prevents Akt-mediated inhibition of MuRF1 and MAFbx upregulation. Our study thus defines a previously uncharacterized function for Akt, which has important therapeutic relevance: Akt is not only capable of activating prosynthetic pathways, as previously demonstrated, but is simultaneously and dominantly able to suppress catabolic pathways, allowing it to prevent glucocorticoid and denervation-induced muscle atrophy.

                Author and article information

                Author notes

                R. Sanders Williams is Dean of the School of Medicine at Duke University, Durham, North Carolina, United States of America. His research interests are centered on the molecular biology of skeletal and cardiac muscle. Williams E. Kraus is Associate Professor of Medicine at Duke University, Durham, North Carolina, United States of America. His research interests are centered on the genetic determinants of cardiovascular disease and studies of exercise as a preventive and therapeutic modality in humans.

                Competing Interests: The authors declare that they have no competing interests.

                *To whom correspondence should be addressed. E-mail:
                PLoS Med
                PLoS Medicine
                Public Library of Science (San Francisco, USA)
                March 2005
                29 March 2005
                : 2
                : 3
                Copyright: © 2005 Williams and Kraus. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
                Research in Translation
                Molecular Biology/Structural Biology
                Sports/Exercise Medicine
                Sports and Exercise Medicine



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