Exercise tames the wild side of the Myc network: a hypothesis

Abstract

Gohil K, Brooks GA. Exercise tames the wild side of the Myc network: a hypothesis. Am J Physiol Endocrinol Metab 303: E18 -E30, 2012. First published April 24, 2012; doi:10.1152/ajpendo.00027.2012We propose that the welldocumented therapeutic actions of repeated physical activities over human lifespan are mediated by the rapidly turning over proto-oncogenic Myc (myelocytomatosis) network of transcription factors. This transcription factor network is unique in utilizing promoter and epigenomic (acetylation/deacetylation, methylation/demethylation) mechanisms for controlling genes that include those encoding intermediary metabolism (the primary source of acetyl groups), mitochondrial functions and biogenesis, and coupling their expression with regulation of cell growth and proliferation. We further propose that remote functioning of the network occurs because there are two arms of this network, which consists of driver cells (e.g., working myocytes) that metabolize carbohydrates, fats, proteins, and oxygen and produce redox-modulating metabolites such as H 2O2, NAD ϩ , and lactate. The exercise-induced products represent autocrine, paracrine, or endocrine signals for target recipient cells (e.g., aortic endothelium, hepatocytes, and pancreatic ␤-cells) in which the metabolic signals are coupled with genomic networks and interorgan signaling is activated. And finally, we propose that lactate, the major metabolite released from working muscles and transported into recipient cells, links the two arms of the signaling pathway. Recently discovered contributions of the Myc network in stem cell development and maintenance further suggest that regular physical activity may prevent age-related diseases such as cardiovascular pathologies, cancers, diabetes, and neurological functions through prevention of stem cell dysfunctions and depletion with aging. Hence, regular physical activities may attenuate the various deleterious effects of the Myc network on health, the wild side of the Myc-network, through modulating transcription of genes associated with glucose and energy metabolism and maintain a healthy human status. myelocytomatosis; lactate shuttle; glycolysis; mitochondrial reticulum; mitochondrial biogenesis; mitochondrial dynamics; exertion; health; chronic diseases REGULAR PHYSICAL ACTIVITIES ameliorate or prevent numerous pathologies frequently associated with aging that include cardiovascular dysfunctions (103,183,200), diabetes (2,17,178,201,214), dementias (41), depression (86,195), and cancers (42, 165). Importantly, physical activity protects against some of these pathologies in a dose-dependent relationship (114,123,222), possibly through targeting the endothelium (173,208,212) that displays tissue-specific phenotypes (125,158,175,191). The molecular basis of this dose-dependent, regular, and "remote action" of skeletal muscle activity on functionally distinct organs needs clarification. In skeletal muscles, the initial and driving organ, transcriptional processes are activated by the exercise stimulus, which ...

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