Remodeling the Skeletal Muscle Extracellular Matrix in Older Age—Effects of Acute Exercise Stimuli on Gene Expression

With advancing age, the skeletal muscle extracellular matrix (ECM) undergoes fibrotic changes that may lead to increased muscle stiffness, injury susceptibility and strength loss. This study tested the potential of different exercises to counter these changes by stimulating the activity of genes associated with ECM remodeling. Twenty-six healthy men (66.9 ± 3.9 years) were stratified to two of four groups, performing unilateral (i) conventional resistance exercise, (ii) conventional resistance exercise followed by self-myofascial release (CEBR), (iii) eccentric-only exercise (ECC) or (iv) plyometric jumps (PLY). The non-trained leg served as control. Six hours post-exercise, vastus lateralis muscle biopsy samples were analyzed for the expression of genes associated with ECM collagen synthesis (COL1A1), matrix metallopeptidases (collagen degradation; MMPs) and peptidase inhibitors (TIMP1). Significant between-group differences were found for MMP3, MMP15 and TIMP1, with the greatest responses in MMP3 and TIMP1 seen in CEBR and in MMP15 in ECC. MMP9 (3.24–3.81-fold change) and COL1A1 (1.47–2.40-fold change) were increased in CEBR and PLY, although between-group differences were non-significant. The expression of ECM-related genes is exercise-specific, with CEBR and PLY triggering either earlier or stronger remodeling than other stimuli. Training studies will test whether execution of such exercises may help counter age-associated muscle fibrosis.

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Contractile activity-specific transcriptome response to acute endurance exercise and training in human skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00449.2018 ◽

2019 ◽

Vol 316 (4) ◽

pp. E605-E614 ◽

Cited By ~ 13

Author(s):

Daniil V. Popov ◽

Pavel A. Makhnovskii ◽

Elena I. Shagimardanova ◽

Guzel R. Gazizova ◽

Evgeny A. Lysenko ◽

...

Keyword(s):

Skeletal Muscle ◽

Transcription Factors ◽

Human Skeletal Muscle ◽

Acute Exercise ◽

Contractile Activity ◽

Vastus Lateralis ◽

Aerobic Exercise Training ◽

Vastus Lateralis Muscle ◽

Transcriptome Response ◽

The One

Reduction in daily activity leads to dramatic metabolic disorders, while regular aerobic exercise training is effective for preventing this problem. The purpose of this study was to identify genes that are directly related to contractile activity in human skeletal muscle, regardless of the level of fitness. Transcriptome changes after the one-legged knee extension exercise in exercised and contralateral nonexercised vastus lateralis muscle of seven men were evaluated by RNA-seq. Transcriptome change at baseline after 2 mo of aerobic training (5/wk, 1 h/day) was evaluated as well. Postexercise changes in the transcriptome of exercised muscle were associated with different factors, including circadian oscillations. To reveal transcriptome response specific for endurance-like contractile activity, differentially expressed genes between exercised and nonexercised muscle were evaluated at 1 and 4 h after the one-legged exercise. The contractile activity-specific transcriptome responses were associated only with an increase in gene expression and were regulated mainly by CREB/ATF/AP1-, MYC/MAX-, and E2F-related transcription factors. Endurance training-induced changes (an increase or decrease) in the transcriptome at baseline were more pronounced than transcriptome responses specific for acute contractile activity. Changes after training were associated with widely different biological processes than those after acute exercise and were regulated by different transcription factors (IRF- and STAT-related factors). In conclusion, adaptation to regular exercise is associated not only with a transient (over several hours) increase in expression of many contractile activity-specific genes, but also with a pronounced change (an increase or decrease) in expression of a large number of genes under baseline conditions.

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Skeletal muscle phosphatidylcholine and phosphatidylethanolamine are related to insulin sensitivity and respond to acute exercise in humans

Journal of Applied Physiology ◽

10.1152/japplphysiol.00664.2015 ◽

2016 ◽

Vol 120 (11) ◽

pp. 1355-1363 ◽

Cited By ~ 26

Author(s):

Sean A. Newsom ◽

Joseph T. Brozinick ◽

Katja Kiseljak-Vassiliades ◽

Allison N. Strauss ◽

Samantha D. Bacon ◽

...

Keyword(s):

Mass Spectrometry ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Acute Exercise ◽

Contractile Function ◽

Vastus Lateralis ◽

Mass Spectrometry Analysis ◽

Vastus Lateralis Muscle ◽

Intravenous Glucose ◽

Exercise In Humans

Several recent reports indicate that the balance of skeletal muscle phosphatidylcholine (PC) and phosphatidylethanolamine (PE) is a key determinant of muscle contractile function and metabolism. The purpose of this study was to determine relationships between skeletal muscle PC, PE and insulin sensitivity, and whether PC and PE are dynamically regulated in response to acute exercise in humans. Insulin sensitivity was measured via intravenous glucose tolerance in sedentary obese adults (OB; n = 14), individuals with type 2 diabetes (T2D; n = 15), and endurance-trained athletes (ATH; n = 15). Vastus lateralis muscle biopsies were obtained at rest, immediately after 90 min of cycle ergometry at 50% maximal oxygen consumption (V̇o2 max), and 2-h postexercise (recovery). Skeletal muscle PC and PE were measured via infusion-based mass spectrometry/mass spectrometry analysis. ATH had greater levels of muscle PC and PE compared with OB and T2D ( P < 0.05), with total PC and PE positively relating to insulin sensitivity (both P < 0.05). Skeletal muscle PC:PE ratio was elevated in T2D compared with OB and ATH ( P < 0.05), tended to be elevated in OB vs. ATH ( P = 0.07), and was inversely related to insulin sensitivity among the entire cohort ( r = −0.43, P = 0.01). Muscle PC and PE were altered by exercise, particularly after 2 h of recovery, in a highly group-specific manner. However, muscle PC:PE ratio remained unchanged in all groups. In summary, total muscle PC and PE are positively related to insulin sensitivity while PC:PE ratio is inversely related to insulin sensitivity in humans. A single session of exercise significantly alters skeletal muscle PC and PE levels, but not PC:PE ratio.

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Exercise adaptation attenuates VEGF gene expression in human skeletal muscle

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.2.h772 ◽

2000 ◽

Vol 279 (2) ◽

pp. H772-H778 ◽

Cited By ~ 93

Author(s):

R. S. Richardson ◽

H. Wagner ◽

S. R. D. Mudaliar ◽

E. Saucedo ◽

R. Henry ◽

...

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Human Skeletal Muscle ◽

Acute Exercise ◽

Vastus Lateralis ◽

Northern Analysis ◽

Endothelial Cell Proliferation ◽

Vastus Lateralis Muscle ◽

Mrna Levels ◽

Exercise Adaptation

Angiogenesis is a component of the multifactoral adaptation to exercise training, and vascular endothelial growth factor (VEGF) is involved in extracellular matrix changes and endothelial cell proliferation. However, there is limited evidence supporting the role of VEGF in the exercise training response. Thus we studied mRNA levels of VEGF, using quantitative Northern analysis, in untrained and trained human skeletal muscle at rest and after a single bout of exercise. Single leg knee-extension provided the acute exercise stimulus and the training modality. Four biopsies were collected from the vastus lateralis muscle at rest in the untrained and trained conditions before and after exercise. Training resulted in a 35% increase in muscle oxygen consumption and an 18% increase in number of capillaries per muscle fiber. At rest, VEGF/18S mRNA levels were similar before (0.38 ± 0.04) and after (1.2 ± 0.4) training. When muscle was untrained, acute exercise greatly elevated VEGF/18S mRNA levels (16.9 ± 6.7). The VEGF/18S mRNA response to acute exercise in the trained state was markedly attenuated (5.4 ± 1.3). These data support the concept that VEGF is involved in exercise-induced skeletal muscle angiogenesis and appears to be subject to a negative feedback mechanism as exercise adaptations occur.

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Transcriptomic Signatures and Upstream Regulation in Human Skeletal Muscle Adapted to Disuse and Aerobic Exercise

International Journal of Molecular Sciences ◽

10.3390/ijms22031208 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1208

Author(s):

Pavel A. Makhnovskii ◽

Roman O. Bokov ◽

Fedor A. Kolpakov ◽

Daniil V. Popov

Keyword(s):

Skeletal Muscle ◽

Transcription Factors ◽

Aerobic Exercise ◽

Human Skeletal Muscle ◽

Acute Exercise ◽

Biological Effects ◽

Vastus Lateralis ◽

Regulation Of Gene Expression ◽

Vastus Lateralis Muscle ◽

Healthy Humans

Inactivity is associated with the development of numerous disorders. Regular aerobic exercise is broadly used as a key intervention to prevent and treat these pathological conditions. In our meta-analysis we aimed to identify and compare (i) the transcriptomic signatures related to disuse, regular and acute aerobic exercise in human skeletal muscle and (ii) the biological effects and transcription factors associated with these transcriptomic changes. A standardized workflow with robust cut-off criteria was used to analyze 27 transcriptomic datasets for the vastus lateralis muscle of healthy humans subjected to disuse, regular and acute aerobic exercise. We evaluated the role of transcriptional regulation in the phenotypic changes described in the literature. The responses to chronic interventions (disuse and regular training) partially correspond to the phenotypic effects. Acute exercise induces changes that are mainly related to the regulation of gene expression, including a strong enrichment of several transcription factors (most of which are related to the ATF/CREB/AP-1 superfamily) and a massive increase in the expression levels of genes encoding transcription factors and co-activators. Overall, the adaptation strategies of skeletal muscle to decreased and increased levels of physical activity differ in direction and demonstrate qualitative differences that are closely associated with the activation of different sets of transcription factors.

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Activation of the erythropoietin receptor in human skeletal muscle

Acta Endocrinologica ◽

10.1530/eje-09-0342 ◽

2009 ◽

Vol 161 (3) ◽

pp. 427-434 ◽

Cited By ~ 34

Author(s):

Helene Rundqvist ◽

Eric Rullman ◽

Carl Johan Sundberg ◽

Helene Fischer ◽

Katarina Eisleitner ◽

...

Keyword(s):

Skeletal Muscle ◽

Satellite Cells ◽

Human Skeletal Muscle ◽

Acute Exercise ◽

Vastus Lateralis ◽

Muscle Fibers ◽

Receptor Activation ◽

Erythropoietin Receptor ◽

Muscle Performance ◽

Vastus Lateralis Muscle

Objective:Erythropoietin receptor (EPOR) expression in non-hematological tissues has been shown to be activated by locally produced and/or systemically delivered EPO. Improved oxygen homeostasis, a well-established consequence of EPOR activation, is very important for human skeletal muscle performance. In the present study we investigate whether human skeletal muscle fibers and satellite cells express EPOR and if it is activated by exercise.Design and methodsTen healthy males performed 65 min of cycle exercise. Biopsies were obtained from the vastus lateralis muscle and femoral arterio-venous differences in EPO concentrations were estimated.ResultsThe EPOR protein was localized in areas corresponding to the sarcolemma and capillaries. Laser dissection identified EPOR mRNA expression in muscle fibers. Also, EPOR mRNA and protein were both detected in human skeletal muscle satellite cells. In the initial part of the exercise bout there was a release of EPO from the exercising leg to the circulation, possibly corresponding to an increased bioavailability of EPO. After exercise, EPOR mRNA and EPOR-associated JAK2 phosphorylation were increased.ConclusionsInteraction with JAK2 is required for EPOR signaling and the increase found in phosphorylation is therefore closely linked to the activation of EPOR. The receptor activation by acute exercise suggests that signaling through EPOR is involved in exercise-induced skeletal muscle adaptation, thus extending the biological role of EPO into the skeletal muscle.

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Effect of consecutive repeated sprint and resistance exercise bouts on acute adaptive responses in human skeletal muscle

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00351.2009 ◽

2009 ◽

Vol 297 (5) ◽

pp. R1441-R1451 ◽

Cited By ~ 62

Author(s):

Vernon G. Coffey ◽

Bozena Jemiolo ◽

Johann Edge ◽

Andrew P. Garnham ◽

Scott W. Trappe ◽

...

Keyword(s):

Skeletal Muscle ◽

Resistance Exercise ◽

Acute Exercise ◽

Vastus Lateralis ◽

Ring Finger ◽

Exercise Bout ◽

Induced Response ◽

Repeated Sprints ◽

Leg Extension ◽

Repeated Sprint

We examined acute molecular responses in skeletal muscle to repeated sprint and resistance exercise bouts. Six men [age, 24.7 ± 6.3 yr; body mass, 81.6 ± 7.3 kg; peak oxygen uptake, 47 ± 9.9 ml·kg−1·min−1; one repetition maximum (1-RM) leg extension 92.2 ± 12.5 kg; means ± SD] were randomly assigned to trials consisting of either resistance exercise (8 × 5 leg extension, 80% 1-RM) followed by repeated sprints (10 × 6 s, 0.75 N·m torque·kg−1) or vice-versa. Muscle biopsies from vastus lateralis were obtained at rest, 15 min after each exercise bout, and following 3-h recovery to determine early signaling and mRNA responses. There was divergent exercise order-dependent phosphorylation of p70 S6K (S6K). Specifically, initial resistance exercise increased S6K phosphorylation (∼75% P < 0.05), but there was no effect when resistance exercise was undertaken after sprints. Exercise decreased IGF-I mRNA following 3-h recovery (∼50%, P = 0.06) independent of order, while muscle RING finger mRNA was elevated with a moderate exercise order effect ( P < 0.01). When resistance exercise was followed by repeated sprints PGC-1α mRNA was increased (REX1-SPR2; P = 0.02) with a modest distinction between exercise orders. Repeated sprints may promote acute interference on resistance exercise responses by attenuating translation initiation signaling and exacerbating ubiquitin ligase expression. Indeed, repeated sprints appear to generate the overriding acute exercise-induced response when undertaking concurrent repeated sprint and resistance exercise. Accordingly, we suggest that sprint-activities are isolated from resistance training and that adequate recovery time is considered within periodized training plans that incorporate these divergent exercise modes.

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Influence of ageing and essential amino acids on quantitative patterns of troponin T alternative splicing in human skeletal muscle

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2014-0568 ◽

2015 ◽

Vol 40 (8) ◽

pp. 788-796 ◽

Cited By ~ 4

Author(s):

Joel Coble ◽

Rudolf J. Schilder ◽

Arthur Berg ◽

Micah J. Drummond ◽

Blake B. Rasmussen ◽

...

Keyword(s):

Skeletal Muscle ◽

Amino Acids ◽

Alternative Splicing ◽

Resistance Exercise ◽

Troponin T ◽

Vastus Lateralis ◽

Essential Amino Acids ◽

Muscle Performance ◽

Muscle Quality ◽

Vastus Lateralis Muscle

Ageing is associated with a loss of skeletal muscle performance, a condition referred to as sarcopenia. In part, the age-related reduction in performance is due to a selective loss of muscle fiber mass, but mass-independent effects have also been demonstrated. An important mass-independent determinant of muscle performance is the pattern of expression of isoforms of proteins that participate in muscle contraction (e.g., the troponins). In the present study, we tested the hypothesis that ageing impairs alternative splicing of the pre-mRNA encoding fast skeletal muscle troponin T (TNNT3) in human vastus lateralis muscle. Furthermore, we hypothesized that resistance exercise alone or in combination with consumption of essential amino acids would attenuate age-associated effects on TNNT3 alternative splicing. Our results indicate that ageing negatively affects the pattern of TNNT3 alternative splicing in a manner that correlates quantitatively with age-associated reductions in muscle performance. Interestingly, whereas vastus lateralis TNNT3 alternative splicing was unaffected by a bout of resistance exercise 24 h prior to muscle biopsy, ingestion of a mixture of essential amino acids after resistance exercise resulted in a significant shift in the pattern of TNNT3 splice form expression in both age groups to one predicted to promote greater muscle performance. We conclude that essential amino acid supplementation after resistance exercise may provide a means to reduce impairments in skeletal muscle quality during ageing in humans.

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Impact of resistance exercise during bed rest on skeletal muscle sarcopenia and myosin isoform distribution

Journal of Applied Physiology ◽

10.1152/jappl.1998.84.1.157 ◽

1998 ◽

Vol 84 (1) ◽

pp. 157-163 ◽

Cited By ~ 163

Author(s):

Marcas M. Bamman ◽

Mark S. F. Clarke ◽

Daniel L. Feeback ◽

Robert J. Talmadge ◽

Bruce R. Stevens ◽

...

Keyword(s):

Skeletal Muscle ◽

Resistance Exercise ◽

Vastus Lateralis ◽

Bed Rest ◽

Vastus Lateralis Muscle ◽

Neural Activation ◽

Type I ◽

Cross Sectional ◽

Maximum Voluntary Isometric Contraction ◽

Leg Press

Bamman, Marcas M., Mark S. F. Clarke, Daniel L. Feeback, Robert J. Talmadge, Bruce R. Stevens, Steven A. Lieberman, and Michael C. Greenisen. Impact of resistance exercise during bed rest on skeletal muscle sarcopenia and myosin isoform distribution. J. Appl. Physiol. 84(1): 157–163, 1998.—Because resistance exercise (REx) and bed-rest unloading (BRU) are associated with opposing adaptations, our purpose was to test the efficacy of REx against the effects of 14 days of BRU on the knee-extensor muscle group. Sixteen healthy men were randomly assigned to no exercise (NoEx; n = 8) or REx ( n = 8). REx performed five sets of leg press exercise with 80–85% of one repetition maximum (1 RM) every other day during BRU. Muscle samples were removed from the vastus lateralis muscle by percutaneous needle biopsy. Myofiber distribution was determined immunohistochemically with three monoclonal antibodies against myosin heavy chain (MHC) isoforms (I, IIa, IIx). MHC distribution was further assessed by quantitative gel electrophoresis. Dynamic 1-RM leg press and unilateral maximum voluntary isometric contraction (MVC) were determined. Maximal neural activation (root mean squared electromyogram) and rate of torque development (RTD) were measured during MVC. Reductions ( P < 0.05) in type I (15%) and type II (17%) myofiber cross-sectional areas were found in NoEx but not in REx. Electrophoresis revealed no changes in MHC isoform distribution. The percentage of type IIx myofibers decreased ( P < 0.05) in REx from 9 to 2% and did not change in NoEx. 1 RM was reduced ( P < 0.05) by 9% in NoEx but was unchanged in REx. MVC fell by 15 and 13% in NoEx and REx, respectively. The agonist-to-antagonist root mean squared electromyogram ratio decreased ( P < 0.05) 19% in REx. RTD slowed ( P < 0.05) by 54% in NoEx only. Results indicate that REx prevented BRU-induced myofiber atrophy and also maintained training-specific strength. Unlike spaceflight, BRU did not induce shifts in myosin phenotype. The reported benefits of REx may prove useful in prescribing exercise for astronauts in microgravity.

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Effects of Acute and Chronic Resistance Exercise on the Skeletal Muscle Metabolome

10.21203/rs.3.rs-1072544/v1 ◽

2021 ◽

Author(s):

Sebastian Gehlert ◽

Patrick Weinisch ◽

Werner Römisch-Margl ◽

Richard T. Jaspers ◽

Anna Artati ◽

...

Keyword(s):

Skeletal Muscle ◽

Resistance Training ◽

Resistance Exercise ◽

Human Skeletal Muscle ◽

Muscle Hypertrophy ◽

Acute Exercise ◽

Vastus Lateralis ◽

Fibre Diameter ◽

Muscle Metabolism ◽

Type I

Abstract Resistance training promotes metabolic health and stimulates muscle hypertrophy, but the precise routes by which resistance exercise (RE) conveys these health benefits is largely unknown. Aim: To investigate how acute RE affects human skeletal muscle metabolism. Methods: We collected vastus lateralis biopsies from six healthy male untrained volunteers at rest, before the first of 13 RE training sessions, and 45 min after the first and last bouts of RE. Biopsies were analysed using untargeted mass spectrometry-based metabolomics. Results: We measured 617 metabolites covering a broad range of metabolic pathways. In the untrained state RE altered 33 metabolites, including increased 3-methylhistidine and 1-carboxylethylvaline, suggesting increased protein breakdown, as well as metabolites linked to ATP (xanthosine) and NAD (N1-methyl-2-pyridone-5-carboxamide) metabolism; the bile acid chenodeoxycholate also increased in response to RE in muscle opposing previous findings in blood. Resistance training led to muscle hypertrophy, with slow type I and fast/intermediate type II muscle fibre diameter increasing by 10.7% and 10.4%, respectively. Comparison of post-exercise metabolite levels between trained and untrained state revealed alterations of 46 metabolites, including decreased N-acetylated ketogenic amino acids and increased beta-citrylglutamate which might support growth. Only five of the metabolites that changed after acute exercise in the untrained state were altered after chronic training, indicating that training induces multiple metabolic changes not directly related to the acute exercise response. Conclusion: The human skeletal muscle metabolome is sensitive towards acute RE in the trained and untrained states and reflects a broad range of adaptive processes in response to repeated stimulation.

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The influence of physical training on the angiopoietin and VEGF-A systems in human skeletal muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.01103.2006 ◽

2007 ◽

Vol 103 (3) ◽

pp. 1012-1020 ◽

Cited By ~ 44

Author(s):

T. Gustafsson ◽

H. Rundqvist ◽

J. Norrbom ◽

E. Rullman ◽

E. Jansson ◽

...

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Human Skeletal Muscle ◽

Acute Exercise ◽

Vastus Lateralis ◽

Exercise Bout ◽

Voluntary Exercise ◽

Vastus Lateralis Muscle ◽

Mrna Levels ◽

Ki 67

Eleven subjects performed one-legged exercise four times per week for 5 wk. The subjects exercised one leg for 45 min with restricted blood flow (R leg), followed by exercise with the other leg at the same absolute workload with unrestricted blood flow (UR leg). mRNA and protein expression were measured in biopsies from the vastus lateralis muscle obtained at rest before the training period, after 10 days, and after 5 wk of training, as well as 120 min after the first and last exercise bouts. Basal Ang-2 and Tie-1 mRNA levels increased in both legs with training. The Ang-2-to-Ang-1 ratio increased to a greater extent in the R leg. The changes in Ang-2 mRNA were followed by similar changes at the protein level. In the R leg, VEGF-A mRNA expression responded transiently after acute exercise both before and after the 5-wk training program. Over the course of the exercise program, there was a concurrent increase in basal VEGF-A protein and VEGFR-2 mRNA in the R leg. Ki-67 mRNA showed a greater increase in the R leg and the protein was localized to the endothelial cells. In summary, the increased translation of VEGF-A is suggested to be caused by the short mRNA burst induced by each exercise bout. The concurrent increase in the Ang-2-to-Ang-1 ratio and the VEGF-expression combined with the higher level of Ki-67 mRNA in the R leg indicate that changes in these systems are of importance also in nonpathological angiogenic condition such as voluntary exercise in humans. It further establish that hypoxia/ischemia-related metabolic perturbation is likely to be involved as stimuli in this process in human skeletal muscle.

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