Low intrinsic running capacity is associated with reduced skeletal muscle substrate oxidation and lower mitochondrial content in white skeletal muscle

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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A higher mitochondrial content is associated with greater oxidative damage, oxidative defenses, protein synthesis and ATP turnover in resting skeletal muscle

Journal of Experimental Biology ◽

10.1242/jeb.242462 ◽

2021 ◽

Vol 224 (19) ◽

Cited By ~ 1

Author(s):

Julie M. Neurohr ◽

Erik T. Paulson ◽

Stephen T. Kinsey

Keyword(s):

Skeletal Muscle ◽

Oxidative Damage ◽

Aerobic Capacity ◽

Protein Turnover ◽

White Muscle ◽

Primary Source ◽

Volume Density ◽

Mitochondrial Density ◽

Atp Turnover ◽

Red Muscle

ABSTRACT An unavoidable consequence of aerobic metabolism is the production of reactive oxygen species (ROS). Mitochondria have historically been considered the primary source of ROS; however, recent literature has highlighted the uncertainty in primary ROS production sites and it is unclear how variation in mitochondrial density influences ROS-induced damage and protein turnover. Fish skeletal muscle is composed of distinct, highly aerobic red muscle and anaerobic white muscle, offering an excellent model system in which to evaluate the relationship of tissue aerobic capacity and ROS-induced damage under baseline conditions. The present study used a suite of indices to better understand potential consequences of aerobic tissue capacity in red and white muscle of the pinfish, Lagodon rhomboides. Red muscle had a 7-fold greater mitochondrial volume density than white muscle, and more oxidative damage despite also having higher activity of the antioxidant enzymes superoxide dismutase and catalase. The dominant protein degradation system appears to be tissue dependent. Lysosomal degradation markers and autophagosome volume density were greater in white muscle, while ubiquitin expression and 20S proteasome activity were significantly greater in red muscle. However, ubiquitin ligase expression was significantly higher in white muscle. Red muscle had a more than 2-fold greater rate of translation and total ATP turnover than white muscle, results that may be due in part to the higher mitochondrial density and the associated increase in oxidative damage. Together, these results support the concept that an elevated aerobic capacity is associated with greater oxidative damage and higher costs of protein turnover.

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Influence of acclimation temperature on mitochondrial DNA, RNA, and enzymes in skeletal muscle

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.275.3.r905 ◽

1998 ◽

Vol 275 (3) ◽

pp. R905-R912 ◽

Cited By ~ 23

Author(s):

Brendan James Battersby ◽

Christopher D. Moyes

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Dna ◽

Steady State ◽

Muscle Fiber ◽

Copy Number ◽

White Muscle ◽

Fiber Types ◽

Mitochondrial Enzymes ◽

Dna Copy Number ◽

Mitochondrial Content

Skeletal muscle fibers typically undergo modifications in their mitochondrial content, concomitant with alterations in oxidative metabolism that occur during the development of muscle fiber and in response to physiological stimuli. We examined how cold acclimation affects the mitochondrial properties of two fish skeletal muscle fiber types and how the regulators of mitochondrial content differed between tissues. After 2 mo of acclimation to either 4 or 18°C, mitochondrial enzyme activities in both red and white muscle were higher in cold-acclimated fish. No significant differences were detected between acclimation temperatures in the abundance of steady-state mitochondrial mRNA (cytochrome- c oxidase 1, subunit 6 of F0F1-ATPase), rRNA (16S), or DNA copy number. Steady-state mRNA for nuclear-encoded respiratory (adenine nucleotide translocase 1) and glycolytic genes showed high interindividual variability, particularly in the cold-acclimated fish. Although mitochondrial enzymes were 10-fold different between the two muscle types, mitochondrial DNA copy number differed only 4-fold. The relative abundance of mitochondrial mRNA and nuclear mRNA in red and white muscle reflected the differences in copy number of their respective genes. These data suggest that the response to physiological stimuli and determination of tissue-specific mitochondrial properties likely result from the regulation of nuclear-encoded genes.

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Artificial Selection for High Aerobic Capacity is Protective against Weight Gain via Thermogenesis?

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.1073.5 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

Sira Maria Torvinen ◽

Mika Silvennoinen ◽

Maria Mikkonen ◽

Lauren G. Koch ◽

Steven L. Britton ◽

...

Keyword(s):

Weight Gain ◽

Aerobic Capacity ◽

Artificial Selection ◽

Selection For

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EFFECTS OF FEEDING AND FOOD DEPRIVATION ON OXYGEN CONSUMPTION, MUSCLE PROTEIN CONCENTRATION AND ACTIVITIES OF ENERGY METABOLISM ENZYMES IN MUSCLE AND BRAIN OF SHALLOW-LIVING (SCORPAENA GUTTATA) AND DEEP-LIVING (SEBASTOLOBUS ALASCANUS) SCORPAENID FISHES

Journal of Experimental Biology ◽

10.1242/jeb.181.1.213 ◽

1993 ◽

Vol 181 (1) ◽

pp. 213-232 ◽

Cited By ~ 7

Author(s):

T. H. Yang ◽

G. N. Somero

Keyword(s):

Skeletal Muscle ◽

Metabolic Rate ◽

Food Deprivation ◽

Enzyme Activities ◽

Protein Concentration ◽

White Muscle ◽

Muscle Protein ◽

Metabolism Enzymes ◽

Red Muscle ◽

Ad Libitum

The effects of feeding and fasting were examined on the deep-living short-spine thornyhead (Sebastolobus alascanus) and the confamilial shallow-living spotted scorpionfish (Scorpaena guttata) to determine whether the low metabolic rate of the deeper-living species was in part a consequence of food deprivation in its habitat. Laboratory acclimation for periods of 90–115 days under either ad libitum feeding or complete fasting did not lead to similar rates of respiration in individuals of the two species held under identical conditions. Respiration of fish fed ad libitum was 52 % (S. guttata) or 68 % (S. alascanus) higher than for fasted fish of the same species. Furthermore, the metabolic rates of freshly collected specimens of S. alascanus resembled those of laboratory-fasted fish. In white skeletal muscle, both total protein concentration and the activities of four enzymes of ATP metabolism, lactate dehydrogenase (LDH) and pyruvate kinase (PK) of glycolysis, malate dehydrogenase (MDH) and citrate synthase (CS, a citric acid cycle indicator), were lower in S. alascanus than in S. guttata. Within a species, protein concentration and activities of the four enzymes in white muscle, but not in brain, were higher in fed than in starved fish, although these differences were greater in S. alascanus than in S. guttata. During fasting, LDH and PK activity in white muscle of S. alascanus decreased much more than MDH and CS activity; decreases in enzyme activities in red muscle were smaller than those in white muscle. Activities of enzymes in white skeletal muscle of field-collected S. alascanus generally resembled those of the fasted specimens. In contrast, red muscle of field- collected S. alascanus, compared with that of either fed or starved laboratory-held specimens, had a highly glycolytic poise (high LDH and PK activities relative to MDH and CS activities), which may suggest that muscle enzyme activities in the field-collected fish reflect adaptation to the low oxygen level in its adult habitat, the oxygen minimum layer. The strong correlations found between tissue biochemical properties and respiration rate allow us to develop a predictive index for metabolic rate from simple biochemical analyses, e.g. white muscle protein content or CS activity. We conclude that the low metabolic rate of S. alascanus is due to at least four depth-related factors: reduced abundance of food, low temperature, low ambient oxygen concentration and darkness, which may select for reduced locomotory activity.

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Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqaa072 ◽

2020 ◽

Vol 112 (2) ◽

pp. 413-426 ◽

Cited By ~ 7

Author(s):

Carlijn M E Remie ◽

Kay H M Roumans ◽

Michiel P B Moonen ◽

Niels J Connell ◽

Bas Havekes ◽

...

Keyword(s):

Skeletal Muscle ◽

Body Composition ◽

Insulin Sensitivity ◽

Energy Metabolism ◽

Mitochondrial Function ◽

Dry Weight ◽

Metabolic Health ◽

Men And Women ◽

Nicotinamide Riboside ◽

Wet Weight

ABSTRACT Background Nicotinamide riboside (NR) is an NAD+ precursor that boosts cellular NAD+ concentrations. Preclinical studies have shown profound metabolic health effects after NR supplementation. Objectives We aimed to investigate the effects of 6 wk NR supplementation on insulin sensitivity, mitochondrial function, and other metabolic health parameters in overweight and obese volunteers. Methods A randomized, double-blinded, placebo-controlled, crossover intervention study was conducted in 13 healthy overweight or obese men and women. Participants received 6 wk NR (1000 mg/d) and placebo supplementation, followed by broad metabolic phenotyping, including hyperinsulinemic-euglycemic clamps, magnetic resonance spectroscopy, muscle biopsies, and assessment of ex vivo mitochondrial function and in vivo energy metabolism. Results Markers of increased NAD+ synthesis—nicotinic acid adenine dinucleotide and methyl nicotinamide—were elevated in skeletal muscle after NR compared with placebo. NR increased body fat-free mass (62.65% ± 2.49% compared with 61.32% ± 2.58% in NR and placebo, respectively; change: 1.34% ± 0.50%, P = 0.02) and increased sleeping metabolic rate. Interestingly, acetylcarnitine concentrations in skeletal muscle were increased upon NR (4558 ± 749 compared with 3025 ± 316 pmol/mg dry weight in NR and placebo, respectively; change: 1533 ± 683 pmol/mg dry weight, P = 0.04) and the capacity to form acetylcarnitine upon exercise was higher in NR than in placebo (2.99 ± 0.30 compared with 2.40 ± 0.33 mmol/kg wet weight; change: 0.53 ± 0.21 mmol/kg wet weight, P = 0.01). However, no effects of NR were found on insulin sensitivity, mitochondrial function, hepatic and intramyocellular lipid accumulation, cardiac energy status, cardiac ejection fraction, ambulatory blood pressure, plasma markers of inflammation, or energy metabolism. Conclusions NR supplementation of 1000 mg/d for 6 wk in healthy overweight or obese men and women increased skeletal muscle NAD+ metabolites, affected skeletal muscle acetylcarnitine metabolism, and induced minor changes in body composition and sleeping metabolic rate. However, no other metabolic health effects were observed. This trial was registered at clinicaltrials.gov as NCT02835664

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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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Role of insulin on exercise-induced GLUT-4 protein expression and glycogen supercompensation in rat skeletal muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.00830.2003 ◽

2004 ◽

Vol 96 (2) ◽

pp. 621-627 ◽

Cited By ~ 12

Author(s):

Chia-Hua Kuo ◽

Hyonson Hwang ◽

Man-Cheong Lee ◽

Arthur L. Castle ◽

John L. Ivy

Keyword(s):

Skeletal Muscle ◽

Protein Expression ◽

Muscle Glycogen ◽

White Muscle ◽

Insulin Response ◽

Exercise Session ◽

Carbohydrate Supplementation ◽

Glut 4 ◽

Red Muscle

The purpose of this study was to investigate the role of insulin on skeletal muscle GLUT-4 protein expression and glycogen storage after postexercise carbohydrate supplementation. Male Sprague-Dawley rats were randomly assigned to one of six treatment groups: sedentary control (Con), Con with streptozocin (Stz/C), immediately postexercise (Ex0), Ex0 with Stz (Stz/Ex0), 5-h postexercise (Ex5), and Ex5 with Stz (Stz/Ex5). Rats were exercised by swimming (2 bouts of 3 h) and carbohydrate supplemented immediately after each exercise session by glucose intubation (1 ml of a 50% wt/vol). Stz was administered 72-h before exercise, which resulted in hyperglycemia and elimination of the insulin response to the carbohydrate supplement. GLUT-4 protein of Ex0 rats was 30% above Con in fast-twitch (FT) red and 21% above Con in FT white muscle. In Ex5, GLUT-4 protein was 52% above Con in FT red and 47% above Con in FT white muscle. Muscle glycogen in FT red and white muscle was also increased above Con in Ex5 rats. Neither GLUT-4 protein nor muscle glycogen was increased above Con in Stz/Ex0 or Stz/Ex5 rats. GLUT-4 mRNA in FT red muscle of Ex0 rats was 61% above Con but only 33% above Con in Ex5 rats. GLUT-4 mRNA in FT red muscle of Stz/C and Stz/Ex0 rats was similar but significantly elevated in Ex5/Stz rats. These results suggest that insulin is essential for the increase in GLUT-4 protein expression following postexercise carbohydrate supplementation.

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A METHODOLOGICAL STUDY IN MEASURING T3 AND T4 CONCENTRATION IN RED AND WHITE SKELETAL MUSCLE AND PLASMA OF EUTHYROID RATS

Acta Endocrinologica ◽

10.1530/acta.0.0900081 ◽

1979 ◽

Vol 90 (1) ◽

pp. 81-89 ◽

Cited By ~ 6

Author(s):

J. W. Janssen ◽

C. van Hardeveld ◽

A. A. H. Kassenaar

Keyword(s):

Skeletal Muscle ◽

White Muscle ◽

Female Rats ◽

Normal Female ◽

Tissue Samples ◽

Tissue Extracts ◽

Red Muscle ◽

The Mean ◽

Ethanol Extracts ◽

Altered Thyroid

ABSTRACT T3 and T4 concentrations were determined in plasma and red and white skeletal muscle of the rat. Because of the small tissue samples (± 300 mg), the ultra-sensitive Wick radioimmunoassay (RIA) for serum was adapted for determination in ethanol extracts. The dilution curves of the plasma and tissue extracts showed excellent parallelism with the standard curves for both T3 and T4. The mean T4 level found in female rats (n = 6) was 22.6 ± 5.2 ng/ml in plasma and did not differ significantly between red (1.85 ± 0.28 ng/g) and white (1.90 ± 0.25 ng/g) skeletal muscle. The mean T3 level in 11 normal female rats was 0.629 ± 0.098 ng/ml in the plasma and was significantly higher in the red muscle (2.07 ± 0.26 ng/g) than in the white muscle (1.65 ± 0.20 ng/g). The higher T3 levels found in the red muscle as compared with the white muscle may help to elucidate the different responsiveness of these muscle types observed in altered thyroid states.

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Changes Induced by Physical Activity and Weight Loss in the Morphology of Intermyofibrillar Mitochondria in Obese Men and Women

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-0002 ◽

2006 ◽

Vol 91 (8) ◽

pp. 3224-3227 ◽

Cited By ~ 77

Author(s):

Frederico G. S. Toledo ◽

Simon Watkins ◽

David E. Kelley

Keyword(s):

Physical Activity ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Weight Loss ◽

Insulin Sensitivity ◽

Lifestyle Modification ◽

Vastus Lateralis ◽

Vastus Lateralis Muscle ◽

Mitochondrial Content ◽

The Mean

Abstract Context: In obesity, skeletal muscle insulin resistance may be associated with smaller mitochondria. Objective: Our objective was to examine the effect of a lifestyle-modification intervention on the content and morphology of skeletal muscle mitochondria and its relationship to insulin sensitivity in obese, insulin-resistant subjects. Design: In this prospective interventional study, intermyofibrillar mitochondrial content and size were quantified by transmission electron microscopy with quantitative morphometric analysis of biopsy samples from vastus lateralis muscle. Systemic insulin sensitivity was measured with euglycemic hyperinsulinemic clamps. Setting: The study took place at a university-based clinical research center. Participants: Eleven sedentary, overweight/obese volunteers without diabetes participated in the study. Intervention: Intervention included 16 wk of aerobic training with dietary restriction of 500-1000 kcal/d. Main Outcome Measures: We assessed changes in mitochondrial content and size and changes in insulin sensitivity. Results: The percentage of myofiber volume occupied by mitochondria significantly increased from 3.70 ± 0.31 to 4.87 ± 0.33% after intervention (P = 0.01). The mean individual increase was 42.5 ± 18.1%. There was also a change in the mean cross-sectional mitochondrial area, increasing from a baseline of 0.078 ± 0.007 to 0.091 ± 0.007 μm2 (P < 0.01), a mean increase of 19.2 ± 6.1% per subject. These changes in mitochondrial size and content highly correlated with improvements in insulin resistance (r = 0.68 and 0.72, respectively; P = 0.01). Conclusions: A combined intervention of weight loss and physical activity in previously sedentary obese adults is associated with enlargement of mitochondria and an increase in the mitochondrial content in skeletal muscle. These findings indicate that in obesity with insulin resistance, ultrastructural mitochondrial plasticity is substantially retained and, importantly, that changes in the morphology of mitochondria are associated with improvements in insulin resistance.

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