Transcriptomic adaptation during skeletal muscle habituation to eccentric or concentric exercise training

AbstractEccentric (ECC) and concentric (CON) contractions induce distinct muscle remodelling patterns that manifest early during exercise training, the causes of which remain unclear. We examined molecular signatures of early contraction mode-specific muscle adaptation via transcriptome-wide network and secretome analyses during 2 weeks of ECC- versus CON-specific (downhill versus uphill running) exercise training (exercise ‘habituation’). Despite habituation attenuating total numbers of exercise-induced genes, functional gene-level profiles of untrained ECC or CON were largely unaltered post-habituation. Network analysis revealed 11 ECC-specific modules, including upregulated extracellular matrix and immune profiles plus downregulated mitochondrial pathways following untrained ECC. Of 3 CON-unique modules, 2 were ribosome-related and downregulated post-habituation. Across training, 376 ECC-specific and 110 CON-specific hub genes were identified, plus 45 predicted transcription factors. Secreted factors were enriched in 3 ECC- and/or CON-responsive modules, with all 3 also being under the predicted transcriptional control of SP1 and KLF4. Of 34 candidate myokine hubs, 1 was also predicted to have elevated expression in skeletal muscle versus other tissues: THBS4, of a secretome-enriched module upregulated after untrained ECC. In conclusion, distinct untrained ECC and CON transcriptional responses are dampened after habituation without substantially shifting molecular functional profiles, providing new mechanistic candidates into contraction-mode specific muscle regulation.

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Skeletal muscle adaptations to exercise are not influenced by metformin treatment in humans: secondary analyses of two randomised, clinical trials.

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2021-0194 ◽

2021 ◽

Author(s):

Nanna Skytt Pilmark ◽

Laura Oberholzer ◽

Jens Frey Halling ◽

Jonas M. Kristensen ◽

Christina Pedersen Bønding ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Exercise Training ◽

Human Skeletal Muscle ◽

Acute Exercise ◽

Metformin Treatment ◽

Ampk Activation ◽

Double Blind ◽

Parallel Group ◽

Exercise Induced

Metformin and exercise both improve glycemic control, but in vitro studies have indicated that an interaction between metformin and exercise occurs in skeletal muscle, suggesting a blunting effect of metformin on exercise training adaptations. Two studies (a double-blind, parallel-group, randomized clinical trial conducted in 29 glucose-intolerant individuals and a double-blind, cross-over trial conducted in 15 healthy lean males) were included in this paper. In both studies, the effect of acute exercise +/- metformin treatment on different skeletal muscle variables, previously suggested to be involved in a pharmaco-physiological interaction between metformin and exercise, was assessed. Furthermore, in the parallel-group trial, the effect of 12 weeks of exercise training was assessed. Skeletal muscle biopsies were obtained before and after acute exercise and 12 weeks of exercise training, and mitochondrial respiration, oxidative stress and AMPK activation was determined. Metformin did not significantly affect the effects of acute exercise or exercise training on mitochondrial respiration, oxidative stress or AMPK activation, indicating that the response to acute exercise and exercise training adaptations in skeletal muscle is not affected by metformin treatment. Further studies are needed to investigate whether an interaction between metformin and exercise is present in other tissues, e.g. the gut. Trial registration: ClinicalTrials.gov (NCT03316690 and NCT02951260). Novelty bullets • Metformin does not affect exercise-induced alterations in mitochondrial respiratory capacity in human skeletal muscle • Metformin does not affect exercise-induced alterations in systemic levels of oxidative stress nor emission of reactive oxygen species from human skeletal muscle • Metformin does not affect exercise-induced AMPK activation in human skeletal muscle

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Exercise: Teaching myocytes new tricks

Journal of Applied Physiology ◽

10.1152/japplphysiol.00418.2017 ◽

2017 ◽

Vol 123 (2) ◽

pp. 460-472 ◽

Cited By ~ 9

Author(s):

Scott K. Powers

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Cardiac Myocytes ◽

Endurance Exercise ◽

Ischemia Reperfusion ◽

Muscle Fibers ◽

Cardiac Phenotype ◽

Endurance Exercise Training ◽

Skeletal Muscle Fibers ◽

Exercise Induced

Endurance exercise training promotes numerous cellular adaptations in both cardiac myocytes and skeletal muscle fibers. For example, exercise training fosters changes in mitochondrial function due to increased mitochondrial protein expression and accelerated mitochondrial turnover. Additionally, endurance exercise training alters the abundance of numerous cytosolic and mitochondrial proteins in both cardiac and skeletal muscle myocytes, resulting in a protective phenotype in the active fibers; this exercise-induced protection of cardiac and skeletal muscle fibers is often referred to as “exercise preconditioning.” As few as 3–5 consecutive days of endurance exercise training result in a preconditioned cardiac phenotype that is sheltered against ischemia-reperfusion-induced injury. Similarly, endurance exercise training results in preconditioned skeletal muscle fibers that are resistant to a variety of stresses (e.g., heat stress, exercise-induced oxidative stress, and inactivity-induced atrophy). Many studies have probed the mechanisms responsible for exercise-induced preconditioning of cardiac and skeletal muscle fibers; these studies are important, because they provide an improved understanding of the biochemical mechanisms responsible for exercise-induced preconditioning, which has the potential to lead to innovative pharmacological therapies aimed at minimizing stress-induced injury to cardiac and skeletal muscle. This review summarizes the development of exercise-induced protection of cardiac myocytes and skeletal muscle fibers and highlights the putative mechanisms responsible for exercise-induced protection in the heart and skeletal muscles.

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Understanding Skeletal Muscle Adaptation to Exercise Training in Humans: Contributions from Microarray Studies

Physical Medicine and Rehabilitation Clinics of North America ◽

10.1016/j.pmr.2005.08.018 ◽

2005 ◽

Vol 16 (4) ◽

pp. 859-873 ◽

Cited By ~ 18

Author(s):

Douglas J. Mahoney ◽

Mark A. Tarnopolsky

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Muscle Adaptation ◽

Microarray Studies ◽

Adaptation To Exercise

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PGC-1α mediates exercise-induced skeletal muscle VEGF expression in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00076.2009 ◽

2009 ◽

Vol 297 (1) ◽

pp. E92-E103 ◽

Cited By ~ 75

Author(s):

Lotte Leick ◽

Ylva Hellsten ◽

Joachim Fentz ◽

Stine S. Lyngby ◽

Jørgen F. P. Wojtaszewski ◽

...

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Protein Expression ◽

Protein Content ◽

Acute Exercise ◽

Whole Body ◽

Vegf Expression ◽

Vegf Mrna ◽

Exercise Induced ◽

Vegf Protein

The aim of the present study was to test the hypothesis that PGC-1α is required for exercise-induced VEGF expression in both young and old mice and that AMPK activation leads to increased VEGF expression through a PGC-1α-dependent mechanism. Whole body PGC-1α knockout (KO) and littermate wild-type (WT) mice were submitted to either 1) 5 wk of exercise training, 2) lifelong (from 2 to 13 mo of age) exercise training in activity wheel, 3) a single exercise bout, or 4) 4 wk of daily subcutaneous AICAR or saline injections. In skeletal muscle of PGC-1α KO mice, VEGF protein expression was ∼60–80% lower and the capillary-to-fiber ratio ∼20% lower than in WT. Basal VEGF mRNA expression was similar in WT and PGC-1α KO mice, but acute exercise and AICAR treatment increased the VEGF mRNA content in WT mice only. Exercise training of young mice increased skeletal muscle VEGF protein expression ∼50% in WT mice but with no effect in PGC-1α KO mice. Furthermore, a training-induced prevention of an age-associated decline in VEGF protein content was observed in WT but not in PGC-1α KO muscles. In addition, repeated AICAR treatments increased skeletal muscle VEGF protein expression ∼15% in WT but not in PGC-1α KO mice. This study shows that PGC-1α is essential for exercise-induced upregulation of skeletal muscle VEGF expression and for a training-induced prevention of an age-associated decline in VEGF protein content. Furthermore, the findings suggest an AMPK-mediated regulation of VEGF expression through PGC-1α.

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Effect of acute exercise and exercise training on VEGF splice variants in human skeletal muscle

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00071.2004 ◽

2004 ◽

Vol 287 (2) ◽

pp. R397-R402 ◽

Cited By ~ 45

Author(s):

Lotte Jensen ◽

Henriette Pilegaard ◽

P. Darrell Neufer ◽

Ylva Hellsten

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Human Skeletal Muscle ◽

Acute Exercise ◽

Splice Variants ◽

Knee Extensor ◽

Vastus Lateralis Muscle ◽

Mrna Levels ◽

Vegf Mrna ◽

Exercise Induced

The present study investigated the effect of an acute exercise bout on the mRNA response of vascular endothelial growth factor (VEGF) splice variants in untrained and trained human skeletal muscle. Seven habitually active young men performed one-legged knee-extensor exercise training at an intensity corresponding to ∼70% of the maximal workload in an incremental test five times/week for 4 wk. Biopsies were obtained from the vastus lateralis muscle of the trained and untrained leg 40 h after the last training session. The subjects then performed 3 h of two-legged knee-extensor exercise, and biopsies were obtained from both legs after 0, 2, 6, and 24 h of recovery. Real-time PCR was used to examine the expression of VEGF mRNA containing exon 1 and 2 (all VEGF isoforms), exon 6 or exon 7, and VEGF165mRNA. Acute exercise induced an increase ( P < 0.05) in total VEGF mRNA levels as well as VEGF165and VEGF splice variants containing exon 7 at 0, 2, and 6 h of recovery. The increase in VEGF mRNA was higher in the untrained than in the trained leg ( P < 0.05). The results suggest that in human skeletal muscle, acute exercise increases total VEGF mRNA, an increase that appears to be explained mainly by an increase in VEGF165mRNA. Furthermore, 4 wk of training attenuated the exercise-induced response in skeletal muscle VEGF165mRNA.

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Vascular remodelling in human skeletal muscle

Biochemical Society Transactions ◽

10.1042/bst20110720 ◽

2011 ◽

Vol 39 (6) ◽

pp. 1628-1632 ◽

Cited By ~ 38

Author(s):

Thomas Gustafsson

Keyword(s):

Skeletal Muscle ◽

Cell Types ◽

Model Systems ◽

Limited Information ◽

Muscle Adaptation ◽

Multiple Systems ◽

Sprouting Angiogenesis ◽

Capillary Growth ◽

Ecm Extracellular Matrix ◽

Exercise Induced

Exercise-induced angiogenesis in skeletal muscle involves both non-sprouting and sprouting angiogenesis and results from the integrated responses of multiple systems and stimuli. VEGF-A (vascular endothelial growth factor A) levels are increased in exercised muscle and have been demonstrated to be critical for exercise-induced capillary growth. Only limited information is available regarding the role of other angiogenic and angiostatic factors in exercise, but changes in the angiopoietin family following repetitive bouts of exercise occur in a pattern that is favourable for angiogenesis. Results from other angiogenic model systems, indicate that miRNAs (microRNAs) are important factors in the regulation of angiogenesis and thus to explore their role as regulators of exercise induced angiogenesis will be an important avenue of study in the future. ECM (extracellular matrix) remodelling and activation of MMPs (matrix metalloproteinases) are, to some extent, overlooked players in skeletal muscle adaptation. Degradation of ECM proteins liberates angiogenic factors from immobilized matrix stores and make cell migration possible. In fact, it is known that MMPs become activated by a single bout of exercise in humans, rapid interstitial changes occur long before any changes in gene transcription could result in protein synthesis and inhibition of MMP activity completely abolishes sprouting angiogenesis. A growing body of evidence suggests that circulating and resident progenitor cells, in addition to other cell types located in skeletal muscle tissue, participate in skeletal muscle angiogenesis by various mechanisms. However, more studies are needed before these can be confirmed as mechanisms of exercise-induced capillary growth.

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Effects of Exercise-Induced ROS on the Pathophysiological Functions of Skeletal Muscle

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/3846122 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

Fan Wang ◽

Xin Wang ◽

Yiping Liu ◽

Zhenghong Zhang

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Acute Exercise ◽

Redox System ◽

The Body ◽

Muscle Adaptation ◽

Exercise Induced ◽

And Function ◽

Stress Fatigue

Oxidative stress is the imbalance of the redox system in the body, which produces excessive reactive oxygen species, leads to multiple cellular damages, and closely relates to some pathological conditions, such as insulin resistance and inflammation. Meanwhile, exercise as an external stimulus of oxidative stress causes the changes of pathophysiological functions in the tissues and organs, including skeletal muscle. Exercise-induced oxidative stress is considered to have different effects on the structure and function of skeletal muscle. Long-term regular or moderate exercise-induced oxidative stress is closely related to the formation of muscle adaptation, while excessive free radicals produced by strenuous or acute exercise can cause muscle oxidative stress fatigue and damage, which impacts exercise capacity and damages the body’s health. The present review systematically summarizes the relationship between exercise-induced oxidative stress and the adaptions, damage, and fatigue in skeletal muscle, in order to clarify the effects of exercise-induced oxidative stress on the pathophysiological functions of skeletal muscle.

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Effects of exercise training on plasma lipids and lipoproteins in rats

Journal of Applied Physiology ◽

10.1152/jappl.1985.58.2.612 ◽

1985 ◽

Vol 58 (2) ◽

pp. 612-618 ◽

Cited By ~ 12

Author(s):

A. E. Pels ◽

T. P. White ◽

W. D. Block

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Plasma Lipids ◽

Plasma Lipid ◽

Density Lipoprotein ◽

Oxidative Capacity ◽

Control Group ◽

High Cholesterol Diet ◽

Exercise Induced ◽

Lipids And Lipoproteins

We studied the effects of exercise training on plasma lipid and lipoprotein concentrations of rats on a high-fat and high-cholesterol diet. Twelve weeks of training occurred at moderate [Mod-Exer, 70% peak O2 consumption (VO2)] and high (High-Exer, 82% peak VO2) intensities. The duration of daily training sessions was adjusted to maintain equivalent energy expenditure between groups. Following training, body weight and lean body mass were 10% lower in the High-Exer group than the Mod-Exer or control groups. Compared with control values, carcass fat content was 33% lower for both trained groups. The oxidative capacity of skeletal muscle was approximately 30% greater in the trained groups compared with the control group. Total cholesterol, high density lipoprotein cholesterol, and total triglyceride concentrations in plasma were not different between the trained groups, but were 33–47% lower compared with the control group. The exercise-induced changes in plasma lipid and lipoprotein concentrations may be a result of a change in preferred substrate utilization in skeletal muscle toward a greater oxidation of lipid.

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