Passive Heat Therapy in Sedentary Humans Improves Aerobic Capacity and Insulin Sensitivity via Increases in Skeletal Muscle Capillarisation and eNOS

Chronic metabolic diseases develop from the complex interaction of environmental and genetic factors, although the extent to which each contributes to these disorders is unknown. Here, we test the hypothesis that artificial selection for low intrinsic aerobic running capacity is associated with reduced skeletal muscle metabolism and impaired metabolic health. Rat models for low- (LCR) and high- (HCR) intrinsic running capacity were derived from genetically heterogeneous N:NIH stock for 20 generations. Artificial selection produced a 530% difference in running capacity between LCR/HCR, which was associated with significant functional differences in glucose and lipid handling by skeletal muscle, as assessed by hindlimb perfusion. LCR had reduced rates of skeletal muscle glucose uptake (∼30%; P = 0.04), glucose oxidation (∼50%; P = 0.04), and lipid oxidation (∼40%; P = 0.02). Artificial selection for low aerobic capacity was also linked with reduced molecular signaling, decreased muscle glycogen, and triglyceride storage, and a lower mitochondrial content in skeletal muscle, with the most profound changes to these parameters evident in white rather than red muscle. We show that a low intrinsic aerobic running capacity confers reduced insulin sensitivity in skeletal muscle and is associated with impaired markers of metabolic health compared with high intrinsic running capacity. Furthermore, selection for high running capacity, in the absence of exercise training, endows increased skeletal muscle insulin sensitivity and oxidative capacity in specifically white muscle rather than red muscle. These data provide evidence that differences in white muscle may have a role in the divergent aerobic capacity observed in this generation of LCR/HCR.

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Human skeletal muscle mitochondrial dynamics in relation to oxidative capacity and insulin sensitivity

Diabetologia ◽

10.1007/s00125-020-05335-w ◽

2020 ◽

Author(s):

Alexandre Houzelle ◽

Johanna A. Jörgensen ◽

Gert Schaart ◽

Sabine Daemen ◽

Nynke van Polanen ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Quality Control ◽

Insulin Sensitivity ◽

Aerobic Capacity ◽

Mitochondrial Dynamics ◽

Oxidative Capacity ◽

Protein Balance ◽

Diabetes Patients

Abstract Aims/hypothesis Mitochondria operate in networks, adapting to external stresses and changes in cellular metabolic demand and are subject to various quality control mechanisms. On the basis of these traits, we here hypothesise that the regulation of mitochondrial networks in skeletal muscle is hampered in humans with compromised oxidative capacity and insulin sensitivity. Methods In a cross-sectional design, we compared four groups of participants (selected from previous studies) ranging in aerobic capacity and insulin sensitivity, i.e. participants with type 2 diabetes (n = 11), obese participants without diabetes (n = 12), lean individuals (n = 10) and endurance-trained athletes (n = 12); basal, overnight fasted muscle biopsies were newly analysed for the current study and we compared the levels of essential mitochondrial dynamics and quality control regulatory proteins in skeletal muscle tissue. Results Type 2 diabetes patients and obese participants were older than lean participants and athletes (58.6 ± 4.0 and 56.7 ± 7.2 vs 21.8 ± 2.5 and 25.1 ± 4.3 years, p < 0.001, respectively) and displayed a higher BMI (32.4 ± 3.7 and 31.0 ± 3.7 vs 22.1 ± 1.8 and 21.0 ± 1.5 kg/m2, p < 0.001, respectively) than lean individuals and endurance-trained athletes. Fission protein 1 (FIS1) and optic atrophy protein 1 (OPA1) protein content was highest in muscle from athletes and lowest in participants with type 2 diabetes and obesity, respectively (FIS1: 1.86 ± 0.79 vs 0.79 ± 0.51 AU, p = 0.002; and OPA1: 1.55 ± 0.64 vs 0.76 ± 0.52 AU, p = 0.014), which coincided with mitochondrial network fragmentation in individuals with type 2 diabetes, as assessed by confocal microscopy in a subset of type 2 diabetes patients vs endurance-trained athletes (n = 6). Furthermore, lean individuals and athletes displayed a mitonuclear protein balance that was different from obese participants and those with type 2 diabetes. Mitonuclear protein balance also associated with heat shock protein 60 (HSP60) protein levels, which were higher in athletes when compared with participants with obesity (p = 0.048) and type 2 diabetes (p = 0.002), indicative for activation of the mitochondrial unfolded protein response. Finally, OPA1, FIS1 and HSP60 correlated positively with aerobic capacity (r = 0.48, p = 0.0001; r = 0.55, p < 0.001 and r = 0.61, p < 0.0001, respectively) and insulin sensitivity (r = 0.40, p = 0.008; r = 0.44, p = 0.003 and r = 0.48, p = 0.001, respectively). Conclusions/interpretation Collectively, our data suggest that mitochondrial dynamics and quality control in skeletal muscle are linked to oxidative capacity in humans, which may play a role in the maintenance of muscle insulin sensitivity. Clinical Trial registry numbers NCT00943059, NCT01298375 and NL1888

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Passive heat therapy in sedentary humans increases skeletal muscle capillarization and eNOS content but not mitochondrial density or GLUT4 content

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00816.2018 ◽

2019 ◽

Vol 317 (1) ◽

pp. H114-H123 ◽

Cited By ~ 16

Author(s):

Katie Hesketh ◽

Sam O. Shepherd ◽

Juliette A. Strauss ◽

David A. Low ◽

Robert J. Cooper ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Glucose Transporter ◽

Whole Body ◽

Moderate Intensity ◽

Continuous Training ◽

Mitochondrial Density ◽

Heat Therapy ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Passive heat therapy (PHT) has been proposed as an alternative intervention to moderate-intensity continuous training (MICT) in individuals who are unable or unwilling to exercise. This study aimed to make the first comparison of the effect of PHT and MICT on 1) skeletal muscle capillarization and endothelial-specific endothelial nitric oxide synthase (eNOS) content and 2) mitochondrial density, glucose transporter 4 (GLUT4), and intramuscular triglyceride (IMTG) content. Twenty young sedentary males (21 ± 1 yr, body mass index 25 ± 1 kg/m2) were allocated to either 6 wk of PHT ( n = 10; 40–50 min at 40°C in a heat chamber, 3×/wk) or MICT ( n = 10; time-matched cycling at ~65% V̇o2peak). Muscle biopsies were taken from the vastus lateralis muscle before and after training. Immunofluorescence microscopy was used to assess changes in skeletal muscle mitochondrial density (mitochondrial marker cytochrome c oxidase subunit 4), GLUT4, and IMTG content, capillarization, and endothelial-specific eNOS content. V̇o2peakand whole body insulin sensitivity were also assessed. PHT and MICT both increased capillary density (PHT 21%; MICT 12%), capillary-fiber perimeter exchange index (PHT 15%; MICT 12%) ( P < 0.05), and endothelial-specific eNOS content (PHT 8%; MICT 12%) ( P < 0.05). However, unlike MICT (mitochondrial density 40%; GLUT4 14%; IMTG content 70%) ( P < 0.05), PHT did not increase mitochondrial density (11%, P = 0.443), GLUT4 (7%, P = 0.217), or IMTG content (1%, P = 0.957). Both interventions improved aerobic capacity (PHT 5%; MICT 7%) and whole body insulin sensitivity (PHT 15%; MICT 36%) ( P < 0.05). Six-week PHT in young sedentary males increases skeletal muscle capillarization and eNOS content to a similar extent as MICT; however, unlike MICT, PHT does not affect skeletal muscle mitochondrial density, GLUT4, or IMTG content.NEW & NOTEWORTHY The effect of 6-wk passive heat therapy (PHT) compared with moderate-intensity continuous training (MICT) was investigated in young sedentary males. PHT induced similar increases in skeletal muscle capillarization and endothelial-specific endothelial nitric oxide synthase content to MICT. Unlike MICT, PHT did not improve skeletal muscle mitochondrial density, glucose transporter 4, or intramuscular triglyceride content. These microvascular adaptations were paralleled by improvements in V̇o2peakand insulin sensitivity, suggesting that microvascular adaptations may contribute to functional improvements following PHT.

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Effects of a Botanical Extract from Artemisia dracunculus L. on Insulin Sensitivity of Human Skeletal Muscle Cell Cultures

Planta Medica ◽

10.1055/s-0031-1273665 ◽

2011 ◽

Vol 77 (05) ◽

Author(s):

P Scherp ◽

N Putluri ◽

GJ LeBlanc ◽

WT Cefalu ◽

I Kheterpal

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Muscle Cell ◽

Cell Cultures ◽

Human Skeletal Muscle ◽

Skeletal Muscle Cell ◽

Artemisia Dracunculus ◽

Human Skeletal Muscle Cell ◽

Botanical Extract

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Epigenetic and Metabolic Changes in Skeletal Muscle Underlying the Improvement of Insulin Sensitivity after Bariatric Surgery in Humans

Diabetes ◽

10.2337/db18-156-or ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 156-OR

Author(s):

SOFIYA GANCHEVA ◽

MERIEM OUNI ◽

CHRYSI KOLIAKI ◽

TOMAS JELENIK ◽

DANIEL F. MARKGRAF ◽

...

Keyword(s):

Bariatric Surgery ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Metabolic Changes

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Faculty Opinions recommendation of Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717147862.792403066 ◽

2012 ◽

Author(s):

Ajay Chawla

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Ppar Gamma ◽

Hepatic Insulin Sensitivity ◽

Antidiabetic Effects

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Systemic oxidative stress is associated with lower aerobic capacity and impaired skeletal muscle energy metabolism in heart failure patients

Scientific Reports ◽

10.1038/s41598-021-81736-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Takashi Yokota ◽

Shintaro Kinugawa ◽

Kagami Hirabayashi ◽

Mayumi Yamato ◽

Shingo Takada ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Skeletal Muscle ◽

Energy Metabolism ◽

Aerobic Capacity ◽

Plantar Flexion ◽

Exercise Intolerance ◽

Whole Body ◽

Resonance Spectroscopy ◽

Systemic Oxidative Stress

AbstractOxidative stress plays a role in the progression of chronic heart failure (CHF). We investigated whether systemic oxidative stress is linked to exercise intolerance and skeletal muscle abnormalities in patients with CHF. We recruited 30 males: 17 CHF patients, 13 healthy controls. All participants underwent blood testing, cardiopulmonary exercise testing, and magnetic resonance spectroscopy (MRS). The serum thiobarbituric acid reactive substances (TBARS; lipid peroxides) were significantly higher (5.1 ± 1.1 vs. 3.4 ± 0.7 μmol/L, p < 0.01) and the serum activities of superoxide dismutase (SOD), an antioxidant, were significantly lower (9.2 ± 7.1 vs. 29.4 ± 9.7 units/L, p < 0.01) in the CHF cohort versus the controls. The oxygen uptake (VO2) at both peak exercise and anaerobic threshold was significantly depressed in the CHF patients; the parameters of aerobic capacity were inversely correlated with serum TBARS and positively correlated with serum SOD activity. The phosphocreatine loss during plantar-flexion exercise and intramyocellular lipid content in the participants' leg muscle measured by 31phosphorus- and 1proton-MRS, respectively, were significantly elevated in the CHF patients, indicating abnormal intramuscular energy metabolism. Notably, the skeletal muscle abnormalities were related to the enhanced systemic oxidative stress. Our analyses revealed that systemic oxidative stress is related to lowered whole-body aerobic capacity and skeletal muscle dysfunction in CHF patients.

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Effect of training on insulin binding to rat skeletal muscle sarcolemmal vesicles

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1986.250.5.e570 ◽

1986 ◽

Vol 250 (5) ◽

pp. E570-E575

Author(s):

G. K. Grimditch ◽

R. J. Barnard ◽

S. A. Kaplan ◽

E. Sternlicht

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Exercise Training ◽

Insulin Binding ◽

Whole Body ◽

Rat Skeletal Muscle ◽

Binding Studies ◽

Muscle Enzyme ◽

Intravenous Glucose ◽

High Affinity

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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Exercise training prevents maturation-induced decrease in insulin sensitivity

Journal of Applied Physiology ◽

10.1152/jappl.1996.80.6.1963 ◽

1996 ◽

Vol 80 (6) ◽

pp. 1963-1967 ◽

Cited By ~ 16

Author(s):

N. Nakai ◽

Y. Shimomura ◽

N. Ohsaki ◽

J. Sato ◽

Y. Oshida ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Exercise Training ◽

Infusion Rate ◽

Glucose Transporter ◽

Euglycemic Clamp ◽

Glut 4 ◽

Hindlimb Muscle ◽

Female Wistar Rats ◽

Sensitivity Improvement

We examined the effects of exercise training initiated before maturation or after maturation on insulin sensitivity and glucose transporter GLUT-4 content in membrane fractions of skeletal muscle. Female Wistar rats (4 wk of age) were divided into sedentary and exercise-trained groups. At 12 wk of age, a subset of the trained animals (Tr) was killed along with a subset of sedentary controls (Sed). One-half of the remaining sedentary animals remained sedentary (Sed-Sed) while the other half began exercise training (Sed-Tr). The remaining rats in the original trained group continued to train (Tr-Tr). Euglycemic clamp (insulin infusion rate at 6 mU.kg body wt-1. min-1) was performed at 4, 12, and 27 wk. After euglycemic clamp in all animals except the 4-wk-old, hindlimb (gastrocnemius and part of quadriceps) muscles were removed for preparation of membrane fractions. In sedentary rats, glucose infusion rate (GIR) during euglycemic clamp was decreased from 15.9 mg.kg-1.min-1 at 4 wk of age to 9.8 mg.kg-1.min-1 at 12 wk of age and 9.1 mg.kg-1.min-1 at 27 wk of age. In exercise-trained rats, the GIR was not significantly decreased by maturation (at 12 wk) and further aging (at 27 wk). Initiation of exercise after maturation restored the GIR at 27 wk of age to the same levels as these for the corresponding exercise-trained rats. GLUT-4 content in plasma and intracellular membrane fractions of hindlimb muscle obtained just after euglycemic clamp showed the same trend as the results of GIR. These results suggest that exercise training prevented the maturation-induced decrease in insulin sensitivity. Improvement of insulin sensitivity caused by exercise training was attributed, at least in part, to the increase in insulin-sensitive GLUT-4 on the plasma membrane in skeletal muscle.

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