A transcriptional map of the impact of endurance exercise training on skeletal muscle phenotype

Abstract

The molecular pathways that are activated and contribute to physiological remodeling of skeletal muscle in response to endurance exercise have not been fully characterized. We previously reported that ∼800 gene transcripts are regulated following 6 wk of supervised endurance training in young sedentary males, referred to as the training-responsive transcriptome (TRT) (Timmons JA et al. J Appl Physiol 108: 1487-1496, 2010). Here we utilized this database together with data on biological variation in muscle adaptation to aerobic endurance training in both humans and a novel out-bred rodent model to study the potential regulatory molecules that coordinate this complex network of genes. We identified three DNA sequences representing RUNX1, SOX9, and PAX3 transcription factor binding sites as overrepresented in the TRT. In turn, miRNA profiling indicated that several miRNAs targeting RUNX1, SOX9, and PAX3 were downregulated by endurance training. The TRT was then examined by contrasting subjects who demonstrated the least vs. the greatest improvement in aerobic capacity (low vs. high responders), and at least 100 of the 800 TRT genes were differentially regulated, thus suggesting regulation of these genes may be important for improving aerobic capacity. In high responders, proangiogenic and tissue developmental networks emerged as key candidates for coordinating tissue aerobic adaptation. Beyond RNA-level validation there were several DNA variants that associated with maximal aerobic capacity (Vo(₂max)) trainability in the HERITAGE Family Study but these did not pass conservative Bonferroni adjustment. In addition, in a rat model selected across 10 generations for high aerobic training responsiveness, we found that both the TRT and a homologous subset of the human high responder genes were regulated to a greater degree in high responder rodent skeletal muscle. This analysis provides a comprehensive map of the transcriptomic features important for aerobic exercise-induced improvements in maximal oxygen consumption.

Effects of physical activity on the link between PGC-1a and FNDC5 in muscle, circulating Ιrisin and UCP1 of white adipocytes in humans: A systematic review

“…For example, previous evidence indicates that PGC-1a mRNA accumulates with endurance training, while studies of PGC-1a protein reflect various antibodies that measure distinct molecular entities ranging from 70 to >110 kDa [78][79][80] . Furthermore, mice lacking PGC-1a adapt normally to endurance exercise training, and in humans the PGC-1a regulated gene network does not correlate with aerobic adaptation 69 . Thus any argument that places Irisin as part of the core PGC-1a regulated exercise adaptation program needs to reflect, on both technical and theoretical grounds, that there is great uncertainty of the nature and importance of PGC-1a in exercise and health 81 .…”

“…One of the included studies 20 found no effect of chronic exercise on PGC1a or FNDC5 mRNA in younger adults (despite detecting significant changes in ~1,000 other mRNAs and finding mitochondrial enzyme activity was increased in ~25%) 69 . Similarly, an 8-week resistance exercise program did not alter PGC-1a or FNDC5 mRNA in muscle of young healthy adults 64 .…”

Advances in Exercise, Fitness, and Performance Genomics in 2015

“…Subsequently, from a panel of 3,400 SNPs in the HERITAGE study cohort, several DNA variants showed associations with the trainability of maximal aerobic power. However, after the conservative Bonferroni correction, none of the SNPs remained statistically significant (26). In the rat model, selected from 10 generations of high responders to aerobic training, there was evidence to the effect that in these animals the TRT and a subset of the human high-responder genes were regulated to a greater degree in the high-responder rodents.…”

“…These transcripts were identified as the training-responsive transcriptome (TRT) (43). In the more recent publication, the same group studied the potential regulatory molecules coordinating the complex network of exercise-training regulated genes using different cohorts, including 24 sedentary and healthy men who performed 6 weeks of endurance training (26). In addition, genotyping was performed on 473 white subjects from the HERITAGE cohort (6), and a novel outbred rodent aerobic capacity model was studied.…”

“…These complex but internally consistent data were taken as evidence for a powerful gene expression program that characterizes successful adaptation to aerobic training. Interestingly, the transcripts involved belong mainly to development-, tumor biology-, and immunology-related pathways (26). From a clinical point of view, it will be interesting to see whether these findings, describing a gene-based responder status to regular exercise programs, will be replicated and eventually provide us with the foundation to individualize exercise programs in a preventive or therapeutic context.…”