High intensity aerobic exercise suppresses cancer growth by regulating skeletal muscle-derived oncogenes and tumor suppressors (Lung)
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ABSTRACT: High intensity aerobic exercise (90% of the maximum heart rate) can effectively suppress cancer proliferation in vivo. However, the molecular effect of aerobic exercise and its relevance to cancer prevention remains uninvestigated. The mRNA-sequencing technique (mRNA-seq) can provide a genome-wide depiction of gene expression changes by aerobic exercise. Mice with colorectal cancer were subjected to high intensity aerobic exercise, and mRNA-seq analysis was performed on heart, lung, and skeletal muscle tissues to analyze the molecular effects of the exercise in a genome-wide manner. The skeletal muscle-derived genes with exercise-dependent differential expressions were further evaluated for their effects on colorectal cancer cell viability. Regular and high intensity aerobic physical activity in the mice produced positive results in comprehensive parameters (i.e., food intake, weight, and survival rate) compared to those in the control groups (healthy and cancer with no exercise). A heatmap of differentially expressed genes revealed markedly different expression patterns between these groups. RNA-seq analysis of 23,282 skeletal muscle-derived genes identified a number of anticancer effector genes. Knockdown and overexpression of selected anticancer genes significantly repressed CT26 proliferation by 20% (p<0.05). Our finding based on the aerobic exercise cancer mouses model suggest that the high intensity exercise resulted in a global change in gene expression patterns, particularly those that affect cancer cell viability.
Project description:High intensity aerobic exercise (90% of the maximum heart rate) can effectively suppress cancer proliferation in vivo. However, the molecular effect of aerobic exercise and its relevance to cancer prevention remains uninvestigated. The mRNA-sequencing technique (mRNA-seq) can provide a genome-wide depiction of gene expression changes by aerobic exercise. Mice with colorectal cancer were subjected to high intensity aerobic exercise, and mRNA-seq analysis was performed on heart, lung, and skeletal muscle tissues to analyze the molecular effects of the exercise in a genome-wide manner. The skeletal muscle-derived genes with exercise-dependent differential expressions were further evaluated for their effects on colorectal cancer cell viability. Regular and high intensity aerobic physical activity in the mice produced positive results in comprehensive parameters (i.e., food intake, weight, and survival rate) compared to those in the control groups (healthy and cancer with no exercise). A heatmap of differentially expressed genes revealed markedly different expression patterns between these groups. RNA-seq analysis of 23,282 skeletal muscle-derived genes identified a number of anticancer effector genes. Knockdown and overexpression of selected anticancer genes significantly repressed CT26 proliferation by 20% (p<0.05). Our finding based on the aerobic exercise cancer mouses model suggest that the high intensity exercise resulted in a global change in gene expression patterns, particularly those that affect cancer cell viability.
Project description:High intensity aerobic exercise (90% of the maximum heart rate) can effectively suppress cancer proliferation in vivo. However, the molecular effect of aerobic exercise and its relevance to cancer prevention remains uninvestigated. The mRNA-sequencing technique (mRNA-seq) can provide a genome-wide depiction of gene expression changes by aerobic exercise. Mice with colorectal cancer were subjected to high intensity aerobic exercise, and mRNA-seq analysis was performed on heart, lung, and skeletal muscle tissues to analyze the molecular effects of the exercise in a genome-wide manner. The skeletal muscle-derived genes with exercise-dependent differential expressions were further evaluated for their effects on colorectal cancer cell viability. Regular and high intensity aerobic physical activity in the mice produced positive results in comprehensive parameters (i.e., food intake, weight, and survival rate) compared to those in the control groups (healthy and cancer with no exercise). A heatmap of differentially expressed genes revealed markedly different expression patterns between these groups. RNA-seq analysis of 23,282 skeletal muscle-derived genes identified a number of anticancer effector genes. Knockdown and overexpression of selected anticancer genes significantly repressed CT26 proliferation by 20% (p<0.05). Our finding based on the aerobic exercise cancer mouses model suggest that the high intensity exercise resulted in a global change in gene expression patterns, particularly those that affect cancer cell viability.
Project description:Skeletal muscle adapts to exercise training of various modes, intensities and durations with a programmed gene expression response. This study dissects the independent and combined effects of exercise mode, intensity and duration to identify which exercise has the most positive effects on skeletal muscle health. Full details on exercise groups can be found in: Kraus et al Med Sci Sports Exerc. 2001 Oct;33(10):1774-84 and Bateman et al Am J Cardiol. 2011 Sep 15;108(6):838-44. This study uses a middle aged group of subjects that have 3+ markers of metabolic syndrome. One group remains an inactive control, while 5 groups undergo 9 mo supervised exercise training. Exercise groups are as follows: Inactive control (group B); Mild aerobic exercise - low amount/mod intensity (group A); Moderate aerobic exercise - low amt/vig intensity (group D); High aerobic exercise - high amt/vig intensity (group C); resistance training only (group F); and mod aerobic + resistance training (group E). Each group has 10 subjects (5 men and 5 women), however 3 subjects failed array QC, leaving 8 subjects in group E and 9 subjects in group F. Data were all analyzed pre to post training in a RM ANCOVA, covaried for age and sex or regression to determine genotype/phenotype interactions.
Project description:Although skeletal muscle metabolism is a well-studied physiological process, little is known about how it is regulated at the transcriptional level. The myogenic transcription factor myogenin is required for skeletal muscle development during embryonic and fetal life, but myogenin’s role in adult skeletal muscle is unclear. We sought to determine myogenin’s function in adult muscle metabolism. A Myog conditional allele and Cre-ER transgene were used to delete Myog in adult mice. Mice were analyzed for exercise capacity by involuntary treadmill running. To assess oxidative and glycolytic metabolism, we monitored blood glucose and lactate levels and performed histochemical analysis on muscle fibers. Surprisingly, we found that Myog-deleted mice performed significantly better than controls in high- and low-intensity treadmill running. This enhanced exercise capacity was due to more efficient oxidative metabolism during low-intensity exercise and more efficient glycolytic metabolism during high-intensity exercise. Furthermore, Myog-deleted mice had an enhanced response to long-term voluntary exercise training on running wheels. We identified several candidate genes whose expression was altered in exercise-stressed muscle of mice lacking myogenin. The results suggest that myogenin plays a critical role as a high-level transcriptional regulator to control the energy balance between aerobic and anaerobic metabolism in adult skeletal muscle. We used microarrays to detail the global program of gene expression underlying enhanced exercise endurance associated with myog-deletion and long-term exercise training.
Project description:High-intensity intermittent exercise training (HIIT) has been proposed as an effective approach for improving both anaerobic and aerobic capacities. However, the molecular response of muscles to HIIT remains unknown. We used microarray to examine the effects of HIIT on global gene expression in human skeletal muscle.
Project description:Although skeletal muscle metabolism is a well-studied physiological process, little is known about how it is regulated at the transcriptional level. The myogenic transcription factor myogenin is required for skeletal muscle development during embryonic and fetal life, but myogeninâs role in adult skeletal muscle is unclear. We sought to determine myogeninâs function in adult muscle metabolism. A Myog conditional allele and Cre-ER transgene were used to delete Myog in adult mice. Mice were analyzed for exercise capacity by involuntary treadmill running. To assess oxidative and glycolytic metabolism, we monitored blood glucose and lactate levels and performed histochemical analysis on muscle fibers. Surprisingly, we found that Myog-deleted mice performed significantly better than controls in high- and low-intensity treadmill running. This enhanced exercise capacity was due to more efficient oxidative metabolism during low-intensity exercise and more efficient glycolytic metabolism during high-intensity exercise. Furthermore, Myog-deleted mice had an enhanced response to long-term voluntary exercise training on running wheels. We identified several candidate genes whose expression was altered in exercise-stressed muscle of mice lacking myogenin. The results suggest that myogenin plays a critical role as a high-level transcriptional regulator to control the energy balance between aerobic and anaerobic metabolism in adult skeletal muscle. We used microarrays to detail the global program of gene expression underlying enhanced exercise endurance associated with myog-deletion and long-term exercise training. Mouse gastrocnemius muscles were selected after 6 months of myog-deletion and exercise training for RNA extraction and hybridization on Affymetrix microarrays. We chose 3 wild type and 3 myog-deleted mice that best represented the average of each larger group that was tested during our mouse exercise studies.
Project description:A single bout of exercise induces changes in gene expression in skeletal muscle. Regular exercise results in an adaptive response involving changes in muscle architecture and biochemistry, and is an effective way to manage and prevent common human diseases such as obesity, cardiovascular disorders and type II diabetes. Our study is a transcriptome-wide analysis of skeletal muscle tissue in a large cohort of untrained Thoroughbred horses before and after a bout of high-intensity exercise and again after an extended period of training. We hypothesized that regular high-intensity exercise training primes the transcriptome for the demands of high-intensity exercise.
Project description:In our study, we investigated for contractile activity-specific changes in the transcriptome in untrained and trained (after an aerobic training programme) human skeletal muscle. The second goal was to examine effect of aerobic training on gene expression in muscle at baseline (after long term training). Seven untrained males performed the one-legged knee extension exercise (for 60 min) with the same relative intensity before and after a 2 month aerobic training programme (1 h/day, 5/week). Biopsy samples were taken at rest (baseline condition, 48 h after exercise), 1 and 4 h after the one-legged exercise from m. vastus lateralis of either leg. Comparison of gene expression in exercised leg with that in non-exercised [control] leg allowed us to identify contractile activity-specific genes in both untrained and trained skeletal muscle, i.e., genes that play a key role in adapting to acute exercise, regardless of the level of fitness. RNA-sequencing (84 samples in total; ~47 million reads/sample) was performed by NextSeq 500 and HiSeq 2500 (Illumina). Two months aerobic training increased the aerobic capacity of the knee-extensor muscles (power at anaerobic threshold in the incremental one-legged and cycling tests), the maximum rate of ADP-stimulated mitochondrial respiration in permeabilized muscle fibres and amounts of oxidative phosphorylation proteins. Contractile activity-specific changes in the transcriptome in untrained and trained human skeletal muscle were revealed for the first time. After 2 month aerobic training, transcriptome responses specific for contractile activity in trained muscle substantially decreased relative to those in untrained muscle. We found out that adaptation of skeletal muscle to regular exercise is associated not only with a transient change in the transcriptome after each stress (acute exercise), but also with a marked change in baseline expression of many genes after repeated stress (e.g., long term training).
Project description:The molecular transducers of benefits from different exercise modalities remain incompletely defined. Here we report that 12 weeks of high-intensity aerobic interval (HIIT), resistance (RT), and combined exercise training enhanced insulin sensitivity and lean mass, but only HIIT and combined training improved aerobic capacity and skeletal muscle mitochondrial respiration. HIIT revealed a more robust increase in gene transcripts than other exercise modalities, particularly in older adults, although little overlap with corresponding individual protein abundance was noted. HIIT reversed many age-related differences in the proteome, particularly of mitochondrial proteins in concert with increased mitochondrial protein synthesis. Both RT and HIIT enhanced proteins involved in translational machinery irrespective of age. Only small changes of methylation of DNA promoter regions were observed. We provide evidence for predominant exercise regulation at the translational level, enhancing translational capacity and proteome abundance to explain phenotypic gains in muscle mitochondrial function and hypertrophy in all ages.