Epigenetic rewiring of skeletal muscle enhancers after exercise training supports a role in whole-body function and human health

We examined the hypothesis that the exercise training-induced increase in skeletal muscle insulin sensitivity is mediated by adaptations in insulin binding to sarcolemmal (SL) insulin receptors. Insulin binding studies were performed on rat skeletal muscle SL isolated from control and trained rats. No significant differences were noted between groups in body weight or fat. An intravenous glucose tolerance test showed an increase in whole-body insulin sensitivity with training, and specific D-glucose transport studies on isolated SL vesicles indicated that this was due in part to adaptations in skeletal muscle. Enzyme marker analyses revealed no differences in yield, purity, or contamination of SL membranes between the two groups. Scatchard analyses indicated no significant differences in the number of insulin binding sites per milligram SL protein on the high-affinity (15.0 +/- 4.1 vs. 18.1 +/- 6.4 X 10(9)) or on the low-affinity portions (925 +/- 80 vs. 884 +/- 106 X 10(9)) of the curves. The association constants of the high-affinity (0.764 +/- 0.154 vs. 0.685 +/- 0.264 X 10(9) M-1) and of the low affinity sites (0.0096 +/- 0.0012 vs. 0.0102 +/- 0.0012 X 10(9) M-1) also were similar. These results do not support the hypothesis that the increased sensitivity to insulin after exercise training is due to changes in SL insulin receptor binding.

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Mechanisms underlying absent training-induced improvement in insulin action in lean, hyperandrogenic women with polycystic ovary syndrome (PCOS)

10.2337/figshare.12860540 ◽

2020 ◽

Author(s):

Ada Admin ◽

Solvejg L. Hansen ◽

Kirstine N. Bojsen-Møller ◽

Anne-Marie Lundsgaard ◽

Frederikke L. Hendrich ◽

...

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Exercise Training ◽

Polycystic Ovary Syndrome ◽

Glucose Uptake ◽

Insulin Action ◽

Polycystic Ovary ◽

Whole Body ◽

Ovary Syndrome ◽

Leg Blood Flow

Women with polycystic ovary syndrome (PCOS) have been shown to be less insulin sensitive compared with control women, independent of BMI. Training is associated with molecular adaptations in skeletal muscle improving glucose uptake and metabolism in both healthy and type 2 diabetic individuals. In the present study, lean, hyperandrogenic women with PCOS (n=9) and healthy controls (CON, n=9) completed 14 weeks of controlled and supervised exercise training. In CON, the training intervention increased whole body insulin action by 26% and insulin-stimulated leg glucose uptake by 53%, together with increased insulin-stimulated leg blood flow and a more oxidative muscle fiber type distribution. In PCOS, no such changes were found, despite similar training intensity and improvements in maximal oxygen uptake. In skeletal muscle of CON, but not PCOS, training increased GLUT4 and HKII mRNA and protein expressions. These data suggest that the impaired increase in whole body insulin action in women with PCOS with training is caused by an impaired ability to upregulate key glucose handling proteins for insulin-stimulated glucose uptake in skeletal muscle, and insulin-stimulated leg blood flow. Still, other important benefits of exercise training appeared in women with PCOS, including an improvement of the hyperandrogenic state.

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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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Exercise training in chronic heart failure: improving skeletal muscle O2transport and utilization

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00469.2015 ◽

2015 ◽

Vol 309 (9) ◽

pp. H1419-H1439 ◽

Cited By ~ 81

Author(s):

Daniel M. Hirai ◽

Timothy I. Musch ◽

David C. Poole

Keyword(s):

Quality Of Life ◽

Heart Failure ◽

Skeletal Muscle ◽

Chronic Heart Failure ◽

Exercise Training ◽

Physical Capacity ◽

Exercise Intolerance ◽

Whole Body ◽

Functional Components

Chronic heart failure (CHF) impairs critical structural and functional components of the O2transport pathway resulting in exercise intolerance and, consequently, reduced quality of life. In contrast, exercise training is capable of combating many of the CHF-induced impairments and enhancing the matching between skeletal muscle O2delivery and utilization ( Q̇mO2and V̇mO2, respectively). The Q̇mO2/ V̇mO2ratio determines the microvascular O2partial pressure (PmvO2), which represents the ultimate force driving blood-myocyte O2flux (see Fig. 1). Improvements in perfusive and diffusive O2conductances are essential to support faster rates of oxidative phosphorylation (reflected as faster V̇mO2kinetics during transitions in metabolic demand) and reduce the reliance on anaerobic glycolysis and utilization of finite energy sources (thus lowering the magnitude of the O2deficit) in trained CHF muscle. These adaptations contribute to attenuated muscle metabolic perturbations (e.g., changes in [PCr], [Cr], [ADP], and pH) and improved physical capacity (i.e., elevated critical power and maximal V̇mO2). Preservation of such plasticity in response to exercise training is crucial considering the dominant role of skeletal muscle dysfunction in the pathophysiology and increased morbidity/mortality of the CHF patient. This brief review focuses on the mechanistic bases for improved Q̇mO2/ V̇mO2matching (and enhanced PmvO2) with exercise training in CHF with both preserved and reduced ejection fraction (HFpEF and HFrEF, respectively). Specifically, O2convection within the skeletal muscle microcirculation, O2diffusion from the red blood cell to the mitochondria, and muscle metabolic control are particularly susceptive to exercise training adaptations in CHF. Alternatives to traditional whole body endurance exercise training programs such as small muscle mass and inspiratory muscle training, pharmacological treatment (e.g., sildenafil and pentoxifylline), and dietary nitrate supplementation are also presented in light of their therapeutic potential. Adaptations within the skeletal muscle O2transport and utilization system underlie improvements in physical capacity and quality of life in CHF and thus take center stage in the therapeutic management of these patients.

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Vitamin D Merging into Immune System-Skeletal Muscle Network: Effects on Human Health

Applied Sciences ◽

10.3390/app10165592 ◽

2020 ◽

Vol 10 (16) ◽

pp. 5592

Author(s):

Clara Crescioli

Keyword(s):

Skeletal Muscle ◽

Vitamin D ◽

Immune System ◽

Human Health ◽

Hypovitaminosis D ◽

Vitamin D Supplementation ◽

Whole Body ◽

Protective Effects ◽

Skeletal Muscle Function ◽

Vitamin D Levels

The concept that extra-skeletal functions of vitamin D impact on human health have taken place since quite ago. Among all, the beneficial effects of vitamin D on immune regulation, skeletal muscle function, and metabolism are undeniable. Adequate vitamin D levels maintain the immune system and skeletal muscle metabolism integrity, promoting whole-body homeostasis; hypovitaminosis D associates with the important decline of both tissues and promotes chronic inflammation, which is recognized to underlie several disease developments. Growing evidence shows that the immune system and skeletal muscle reciprocally dialogue, modulating each other’s function. Within this crosstalk, vitamin D seems able to integrate and converge some biomolecular signaling towards anti-inflammatory protective effects. Thus, vitamin D regulation appears even more critical at the immune system-muscle signaling intersection, rather than at the single tissue level, opening to wider/newer opportunities in clinical applications to improve health. This paper aims to focus on the immune system-skeletal muscle interplay as a multifaceted target for vitamin D in health and disease after recalling the main regulatory functions of vitamin D on those systems, separately. Some myokines, particularly relevant within the immune system/skeletal muscle/vitamin D networking, are discussed. Since vitamin D supplementation potentially offers the opportunity to maintain health, comments on this issue, still under debate, are included.

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Changes in fat and skeletal muscle with exercise training in obese adolescents: Comparison of whole-body MRI and dual energy X-ray absorptiometry

Obesity ◽

10.1002/oby.20448 ◽

2013 ◽

Vol 21 (10) ◽

pp. 2063-2071 ◽

Cited By ~ 19

Author(s):

SoJung Lee ◽

Jennifer L. Kuk

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Dual Energy ◽

Whole Body ◽

Whole Body Mri ◽

X Ray ◽

Obese Adolescents

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Effect of aging on response to exercise training in humans: skeletal muscle GLUT-4 and insulin sensitivity

Journal of Applied Physiology ◽

10.1152/jappl.1999.86.6.2019 ◽

1999 ◽

Vol 86 (6) ◽

pp. 2019-2025 ◽

Cited By ~ 96

Author(s):

Julie H. Cox ◽

Ronald N. Cortright ◽

G. Lynis Dohm ◽

Joseph A. Houmard

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Exercise Training ◽

Oxygen Uptake ◽

Maximal Oxygen Uptake ◽

Insulin Action ◽

Whole Body ◽

Sensitivity Index ◽

Intravenous Glucose ◽

Glut 4

The purpose of this study was to compare the effects of short-term exercise training on insulin-responsive glucose transporter (GLUT-4) concentration and insulin sensitivity in young and older individuals. Young and older women [22.4 ± 0.8 (SE) yr, n = 9; and 60.9 ± 1.0 yr, n = 10] and men (20.9 ± 0.9, n = 9; 56.5 ± 1.9 yr, n = 8), respectively, were studied before and after 7 consecutive days of exercise training (1 h/day, ≈75% maximal oxygen uptake). The older groups had more adipose tissue, increased central adiposity, and a lower maximal oxygen uptake. Despite these differences, increases in whole body insulin action (insulin sensitivity index, determined with an intravenous glucose tolerance test and minimal-model analysis) with training were similar regardless of age, in both the women and men (mean increase of 2.2 ± 0.3-fold). This was accompanied by similar relative increases in muscle (vastus lateralis) GLUT-4 protein concentration, irrespective of age (mean increase of 3.1 ± 0.7-fold). Body mass did not change with training in any of the groups. These data suggest that older human skeletal muscle retains the ability to rapidly increase muscle GLUT-4 and improve insulin action with endurance training.

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Exercise training improves mitochondrial respiration and is associated with an altered intramuscular phospholipid signature in women with obesity

Diabetologia ◽

10.1007/s00125-021-05430-6 ◽

2021 ◽

Author(s):

Amy E. Mendham ◽

Julia H. Goedecke ◽

Yingxu Zeng ◽

Steen Larsen ◽

Cindy George ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Exercise Training ◽

Protein Content ◽

Mitochondrial Respiration ◽

Controlled Trial ◽

Peak Oxygen Consumption ◽

Whole Body ◽

Post Intervention ◽

Sphingomyelin Synthase

Abstract Aims/hypothesis We sought to determine putative relationships among improved mitochondrial respiration, insulin sensitivity and altered skeletal muscle lipids and metabolite signature in response to combined aerobic and resistance training in women with obesity. Methods This study reports a secondary analysis of a randomised controlled trial including additional measures of mitochondrial respiration, skeletal muscle lipidomics, metabolomics and protein content. Women with obesity were randomised into 12 weeks of combined aerobic and resistance exercise training (n = 20) or control (n = 15) groups. Pre- and post-intervention testing included peak oxygen consumption, whole-body insulin sensitivity (intravenous glucose tolerance test), skeletal muscle mitochondrial respiration (high-resolution respirometry), lipidomics and metabolomics (mass spectrometry) and lipid content (magnetic resonance imaging and spectroscopy). Proteins involved in glucose transport (i.e. GLUT4) and lipid turnover (i.e. sphingomyelin synthase 1 and 2) were assessed by western blotting. Results The original randomised controlled trial showed that exercise training increased insulin sensitivity (median [IQR]; 3.4 [2.0–4.6] to 3.6 [2.4–6.2] x10−5 pmol l−1 min−1), peak oxygen consumption (mean ± SD; 24.9 ± 2.4 to 27.6 ± 3.4 ml kg−1 min−1), and decreased body weight (84.1 ± 8.7 to 83.3 ± 9.7 kg), with an increase in weight (pre intervention, 87.8± 10.9 to post intervention 88.8 ± 11.0 kg) in the control group (interaction p < 0.05). The current study shows an increase in mitochondrial respiration and content in response to exercise training (interaction p < 0.05). The metabolite and lipid signature at baseline were significantly associated with mitochondrial respiratory capacity (p < 0.05) but were not associated with whole-body insulin sensitivity or GLUT4 protein content. Exercise training significantly altered the skeletal muscle lipid profile, increasing specific diacylglycerol(32:2) and ceramide(d18:1/24:0) levels, without changes in other intermediates or total content of diacylglycerol and ceramide. The total content of cardiolipin, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) increased with exercise training with a decrease in the PC:PE ratios containing 22:5 and 20:4 fatty acids. These changes were associated with content-driven increases in mitochondrial respiration (p < 0.05), but not with the increase in whole-body insulin sensitivity or GLUT4 protein content. Exercise training increased sphingomyelin synthase 1 (p < 0.05), with no change in plasma-membrane-located sphingomyelin synthase 2. Conclusions/interpretation The major findings of our study were that exercise training altered specific intramuscular lipid intermediates, associated with content-driven increases in mitochondrial respiration but not whole-body insulin sensitivity. This highlights the benefits of exercise training and presents putative target pathways for preventing lipotoxicity in skeletal muscle, which is typically associated with the development of type 2 diabetes. Graphical abstract

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Effects of 10 Days of Endurance Exercise Training on the Suppression of Whole Body and Regional Lipolysis by Insulin1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.85.4.6550 ◽

2000 ◽

Vol 85 (4) ◽

pp. 1498-1504

Author(s):

R. C. Hickner ◽

S. B. Racette ◽

E. F. Binder ◽

J. S. Fisher ◽

W. M. Kohrt

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Exercise Training ◽

Endurance Exercise ◽

Premenopausal Women ◽

Whole Body ◽

Obese Women ◽

Endurance Exercise Training ◽

Before And After ◽

Basal Plasma

The aim of this study was to evaluate in premenopausal women (10 sedentary obese women) the effects of 10 days of exercise on the suppression of whole body and regional lipolysis by insulin. Lipolysis was determined using 2H5-glycerol infusion and microdialysis of sc adipose tissue during a two-stage hyperinsulinemic-euglycemic clamp [10 (LO) and 20 (MO) mU/m·min]. Microdialysis probes were positioned in abdominal and femoral sc adipose tissue to monitor interstitial glycerol and blood flow. Basal plasma glycerol was 86.7 ± 17.0 and 100.3 ± 19.8 μmol/L before and after training, respectively (P < 0.05). Plasma glycerol was suppressed to a greater extent after [to 47 ± 5% (LO) and 42 ± 5% (MO) of basal] than before [to 62 ± 8% (LO) and 55 ± 8% (MO) of basal] training. The rate of appearance of glycerol was suppressed to 49 ± 7% and 40 ± 5% of basal during LO and to 38 ± 5% and 30 ± 4% of basal during MO (P < 0.05) before and after training, respectively. There were no differences in the suppression of lipolysis in abdominal as well as femoral sc adipose tissue as evidenced by similar reductions in dialysate glycerol levels before and after training in each of these tissues. The results indicate that the antilipolytic response to insulin can be improved through endurance exercise training. Intraabdominal adipose tissue or skeletal muscle may be the site of improved antilipolytic response to insulin after training, as improvement was not evident in abdominal or femoral sc adipose tissue.

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Muscle Blood Flow and Mitochondrial Function: Influence of Aging

International Journal of Sport Nutrition and Exercise Metabolism ◽

10.1123/ijsnem.12.3.368 ◽

2002 ◽

Vol 12 (3) ◽

pp. 368-378 ◽

Cited By ~ 19

Author(s):

Ronald L. Terjung ◽

Ryszard Zarzeczny ◽

H.T. Yang

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Exercise Training ◽

Muscle Blood Flow ◽

The Elderly ◽

Exchange Capacity ◽

Oxygen Exchange ◽

Whole Body ◽

Tissue Blood Flow ◽

Fiber Types

Skeletal muscle mitochondrial capacity (mito), tissue blood flow (BF) capacity, and oxygen exchange capacity (e.g., DO2) appear to be well matched. The different skeletal muscle fiber types and muscle remodeled, due to inactivity >(e.g., related to aging or disease) or exercise training, exhibit widely differing aerobics capacities (V̇O2max). Yet, there are remarkably coordinated alterations in these 3 parameters in each of these conditions. With such a balance, there is likely shared control among these parameters in limiting (V̇O2max) of muscle, although this is a matter of considerable debate. The reduction in aerobic capacity in elderly can be improved by submaximal aerobic exercise training; this is related to increases in muscle mitochondria concentration and capillarity, but probably not BF capacity, as this is limited by central cardiovascular function. Thus, exercise-induced biochemical adaptations and angiogenesis occur in the elderly. The increase in muscle capillarity likely contributes to the increased oxygen exchange capacity, typical of endurance type training. The increase in [mito] appears essential to realize the increased in muscle V̇O2max with training and amplifies the rate-limiting influence of the muscle’s oxygen exchange capacity. Further, vascular remodeling induced by exercise in the elderly could be effective at improving flow capacity, if limited by peripheral obstruction. Thus, the limits to aerobic function specific to aged muscle appear most influenced by inactivity, whereas central cardiovascular changes impact whole body performance. Some may consider the aged myocyte as a small, inactive, normal myocyte in need of activity!

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