bims-exemet 2021-07-18 papers

bims-exemet

Biomed News

on Exercise metabolism

Issue of 2021–07–18
seven papers selected by
Javier Botella Ruiz, Victoria University

Epigenetic rewiring of skeletal muscle enhancers after exercise training supports a role in whole-body function and human health.
Altered skeletal muscle metabolic pathways, age, systemic inflammation, and low cardiorespiratory fitness associate with improvements in disease activity following high-intensity interval training in persons with rheumatoid arthritis.
Physical Exercise for Human Health.
Metabolic and cardiovascular adaptations to an 8-week lifestyle weight loss intervention in younger and older obese men.
Insulin Resistance in Skeletal Muscle Selectively Protects the Heart in Response to Metabolic Stress.
Metabolomic profiles of being physically active and less sedentary: a critical review.
Regulation of muscle and mitochondrial health by the mitochondrial fission protein Drp1 in aged mice.

Mol Metab. 2021 Jul 09. pii: S2212-8778(21)00135-6. [Epub ahead of print] 101290

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

Kristine Williams, Germán D Carrasquilla, Lars Roed Ingerslev, Mette Yde Hochreuter, Svenja Hansson, Nicolas J Pillon, Ida Donkin, Soetkin Versteyhe, Juleen R Zierath, Tuomas O Kilpeläinen, Romain Barrès.

   OBJECTIVES: Regular physical exercise improves health by reducing the risk of a plethora of chronic disorders. We hypothesized that endurance exercise training remodels the activity of gene enhancers in skeletal muscle, and that this remodeling contributes to the beneficial effects of exercise on human health.
METHODS AND RESULTS: By studying changes in histone modifications, we mapped the genome-wide positions and activities of enhancers in skeletal muscle biopsies collected from young sedentary men before and after 6 weeks of endurance exercise. We identified extensive remodeling of enhancer activities after exercise training, with a large subset of the remodeled enhancers located in the proximity of genes transcriptionally regulated after exercise. By overlapping the position of enhancers with genetic variants, we identified an enrichment of disease-associated genetic variants within the exercise-remodeled enhancers.
CONCLUSION: Our data provide evidence of a functional link between epigenetic rewiring of enhancers to control their activity after exercise training and the modulation of disease risk in humans.

Keywords:  Enhancers; Exercise; GWAS; Skeletal muscle

DOI:  https://doi.org/10.1016/j.molmet.2021.101290
Arthritis Res Ther. 2021 Jul 10. 23(1): 187

Altered skeletal muscle metabolic pathways, age, systemic inflammation, and low cardiorespiratory fitness associate with improvements in disease activity following high-intensity interval training in persons with rheumatoid arthritis.

Brian J Andonian, Andrew Johannemann, Monica J Hubal, David M Pober, Alec Koss, William E Kraus, David B Bartlett, Kim M Huffman.

   BACKGROUND: Exercise training, including high-intensity interval training (HIIT), improves rheumatoid arthritis (RA) inflammatory disease activity via unclear mechanisms. Because exercise requires skeletal muscle, skeletal muscle molecular pathways may contribute. The purpose of this study was to identify connections between skeletal muscle molecular pathways, RA disease activity, and RA disease activity improvements following HIIT.
METHODS: RA disease activity assessments and vastus lateralis skeletal muscle biopsies were performed in two separate cohorts of persons with established, seropositive, and/or erosive RA. Body composition and objective physical activity assessments were also performed in both the cross-sectional cohort and the longitudinal group before and after 10 weeks of HIIT. Baseline clinical assessments and muscle RNA gene expression were correlated with RA disease activity score in 28 joints (DAS-28) and DAS-28 improvements following HIIT. Skeletal muscle gene expression changes with HIIT were evaluated using analysis of covariance and biological pathway analysis.
RESULTS: RA inflammatory disease activity was associated with greater amounts of intramuscular adiposity and less vigorous aerobic exercise (both p < 0.05). HIIT-induced disease activity improvements were greatest in those with an older age, elevated erythrocyte sedimentation rate, low cardiorespiratory fitness, and a skeletal muscle molecular profile indicative of altered metabolic pathways (p < 0.05 for all). Specifically, disease activity improvements were linked to baseline expression of RA skeletal muscle genes with cellular functions to (1) increase amino acid catabolism and interconversion (GLDC, BCKDHB, AASS, PYCR, RPL15), (2) increase glycolytic lactate production (AGL, PDK2, LDHB, HIF1A), and (3) reduce oxidative metabolism via altered beta-oxidation (PXMP2, ACSS2), TCA cycle flux (OGDH, SUCLA2, MDH1B), and electron transport chain complex I function (NDUFV3). The muscle mitochondrial glycine cleavage system (GCS) was identified as critically involved in RA disease activity improvements given upregulation of multiple GCS genes at baseline, while GLDC was significantly downregulated following HIIT.
CONCLUSION: In the absence of physical activity, RA inflammatory disease activity is associated with transcriptional remodeling of skeletal muscle metabolism. Following exercise training, the greatest improvements in disease activity occur in older, more inflamed, and less fit persons with RA. These exercise training-induced immunomodulatory changes may occur via reprogramming muscle bioenergetic and amino acid/protein homeostatic pathways.
TRIAL REGISTRATION: ClinicalTrials.gov , NCT02528344 . Registered on 19 August 2015.

Keywords:  Cardiorespiratory fitness; Disease activity; Exercise training; Gene expression; Inflammation; Metabolism; Rheumatoid arthritis; Skeletal muscle

DOI:  https://doi.org/10.1186/s13075-021-02570-3
Med Sci Sports Exerc. 2021 Apr 01. 53(4): 882

Physical Exercise for Human Health.

DOI: https://doi.org/10.1249/01.mss.0000735220.08496.9d
Am J Physiol Endocrinol Metab. 2021 Jul 12.

Metabolic and cardiovascular adaptations to an 8-week lifestyle weight loss intervention in younger and older obese men.

Julie Vion, Veronika Sramkova, Emilie Montastier, Marie-Adeline Marques, Sylvie Caspar-Bauguil, Thibaut Duparc, Laurent O Martinez, Virginie Bourlier, Isabelle Harant, Dominique Larrouy, Nabila Moussaoui, Sophie Bonnel, Celine Vindis, Cédric Dray, Philippe Valet, Jean Sebastien Saulnier-Blache, Joost Schanstra, Claire Thalamas, Nathalie Viguerie, Cedric Moro, Dominique Langin.

  The number of older obese adults is increasing worldwide. Whether obese adults show similar health benefits in response to lifestyle interventions at different ages is unknown. The study enrolled 25 obese men (BMI 31-39 kg/m2) in two arms according to age (30-40 and 60-70 years old). Participants underwent an 8-week intervention with moderate calorie restriction (~20% below individual energy requirements) and supervised endurance training resulting in ~5% weight loss. Body composition was measured using dual energy X-Ray absorptiometry. Insulin sensitivity was assessed during a hypersinsulinemic euglycemic clamp. Cardiometabolic profile was derived from blood parameters. Subcutaneous fat and vastus lateralis muscle biopsies were used for ex vivo analyses. Two-way repeated-measure ANOVA and linear mixed models were used to evaluate the response to lifestyle intervention and comparison between the two groups. Fat mass was decreased and bone mass was preserved in the two groups after intervention. Muscle mass decreased significantly in older obese men. Cardiovascular risk (Framingham risk score, plasma triglyceride and cholesterol) and insulin sensitivity were greatly improved to a similar extent in the two age groups after intervention. Changes in adipose tissue and skeletal muscle transcriptomes were marginal. Analysis of the differential response to the lifestyle intervention showed tenuous differences between age groups. These data suggest that lifestyle intervention combining calorie restriction and exercise shows similar beneficial effects on cardiometabolic risk and insulin sensitivity in younger and older obese men. However, attention must be paid to potential loss of muscle mass in response to weight loss in older obese men.

Keywords:  Aging; Calorie Restriction; Cardiometabolic risk; Obesity; Physical Exercise

DOI:  https://doi.org/10.1152/ajpendo.00109.2021
Diabetes. 2021 Jul 08. pii: db201212. [Epub ahead of print]

Insulin Resistance in Skeletal Muscle Selectively Protects the Heart in Response to Metabolic Stress.

Dandan Jia, Jun Zhang, Xueling Liu, John-Paul Andersen, Zhenjun Tian, Jia Nie, Yuguang Shi.

Obesity and type 2 diabetes mellitus (T2DM) are the leading causes of cardiovascular morbidity and mortality. Although insulin resistance is believed to underlie these disorders, anecdotal evidence contradicts this common belief. Accordingly, obese patients with cardiovascular disease have better prognoses relative to leaner patients with the same diagnoses, whereas treatment of T2DM patients with thiazolidines, one of the popular insulin sensitizer drugs, significantly increases the risk of heart failure. Using mice with skeletal muscle-specific ablation of the insulin receptor gene (MIRKO), we addressed this paradox by demonstrating that insulin signaling in skeletal muscles specifically mediated crosstalk with the heart, but not other metabolic tissues, to prevent cardiac dysfunction in response to metabolic stress. Despite severe hyperinsulinemia and aggregating obesity, MIRKO mice were protected from myocardial insulin resistance, mitochondrial dysfunction, and metabolic reprogramming in response to diet-induced obesity (DIO). Consequently, the MIRKO mice were also protected from myocardial inflammation, cardiomyopathy, and left ventricle dysfunction. Together, our findings suggest that insulin resistance in skeletal muscle functions as a double-edged sword in metabolic diseases.Obesity and type 2 diabetes mellitus (T2DM) are the leading causes of cardiovascular morbidity and mortality. Although insulin resistance is believed to underlie these disorders, anecdotal evidence contradicts this common belief. Accordingly, obese patients with cardiovascular disease have better prognoses relative to leaner patients with the same diagnoses, whereas treatment of T2DM patients with thiazolidines, one of the popular insulin sensitizer drugs, significantly increases the risk of heart failure. Using mice with skeletal muscle-specific ablation of the insulin receptor gene (MIRKO), we addressed this paradox by demonstrating that insulin signaling in skeletal muscles specifically mediated crosstalk with the heart, but not other metabolic tissues, to prevent cardiac dysfunction in response to metabolic stress. Despite severe hyperinsulinemia and aggregating obesity, MIRKO mice were protected from myocardial insulin resistance, mitochondrial dysfunction, and metabolic reprogramming in response to diet-induced obesity (DIO). Consequently, the MIRKO mice were also protected from myocardial inflammation, cardiomyopathy, and left ventricle dysfunction. Together, our findings suggest that insulin resistance in skeletal muscle functions as a double-edged sword in metabolic diseases.

DOI: https://doi.org/10.2337/db20-1212
Metabolomics. 2021 Jul 10. 17(7): 68

Metabolomic profiles of being physically active and less sedentary: a critical review.

Qu Tian, Abigail E Corkum, Ruin Moaddel, Luigi Ferrucci.

   BACKGROUND: Being physically active has multiple salutary effects on human health, likely mediated by changes in energy metabolism. Recent reviews have summarized metabolomic responses to acute exercise. However, metabolomic profiles of individuals who exercise regularly are heterogeneous.
AIM OF REVIEW: We conducted a systematic review to identify metabolites associated with physical activity (PA), fitness, and sedentary time in community-dwelling adults and discussed involved pathways. Twenty-two studies were eligible because they (1) focused on community-dwelling adults from observational studies; (2) assessed PA, fitness, and/or sedentary time, (3) assessed metabolomics in biofluid, and (4) reported on relationships of metabolomics with PA, fitness, and/or sedentary time.
KEY SCIENTIFIC CONCEPTS OF REVIEW: Several metabolic pathways were associated with higher PA and fitness and less sedentary time, including tricarboxylic acid cycle, glycolysis, aminoacyl-tRNA biosynthesis, urea cycle, arginine biosynthesis, branch-chain amino acids, and estrogen metabolism. Lipids were strongly associated with PA. Cholesterol low-density lipoproteins and triglycerides were lower with higher PA, while cholesterol high-density lipoproteins were higher. Metabolomic profiles of being physically active and less sedentary indicate active skeletal muscle biosynthesis supported by enhanced oxidative phosphorylation and glycolysis and associated with profound changes in lipid and estrogen metabolism. Future longitudinal studies are needed to understand whether these metabolomic changes account for health benefits associated with PA.

Keywords:  Fitness; Metabolomic profile; Metabolomics; Physical activity; Sedentary time

DOI:  https://doi.org/10.1007/s11306-021-01818-y
J Physiol. 2021 Jul 16.

Regulation of muscle and mitochondrial health by the mitochondrial fission protein Drp1 in aged mice.

Maude Dulac, Jean-Philippe Leduc-Gaudet, Marina Cefis, Marie-Belle Ayoub, Olivier Reynaud, Anwar Shams, Alaa Moamer, Marcos Francisco Nery Ferreira, Sabah Na Hussain, Gilles Gouspillou.

   KEY POINTS: The maintenance of mitochondrial integrity is critical for skeletal muscle health. Mitochondrial dynamics play key roles in mitochondrial quality control; however, the exact role that mitochondrial fission plays in the muscle aging process remains unclear. Here we report that both Drp1 knockdown and overexpression late in life in mice is detrimental to skeletal muscle function and mitochondrial health. Drp1 knockdown in 18-month-old mice resulted in severe skeletal muscle atrophy, mitochondrial dysfunction, muscle degeneration/regeneration, oxidative stress, and impaired autophagy. Overexpressing Drp1 in 18-month-old mice resulted in mild skeletal muscle atrophy and decreased mitochondrial quality. Our data indicate that silencing or overexpressing Drp1 late in life is detrimental to skeletal muscle integrity. We conclude that modulating Drp1 expression is unlikely to be a viable approach to counter the muscle aging process.
ABSTRACT: Sarcopenia, the aging-related loss of skeletal muscle mass and function, is a debilitating process negatively impacting s the quality of life of afflicted individuals. Although the mechanisms underlying sarcopenia are still only partly understood, impairments in mitochondrial dynamics, and specifically mitochondrial fission, have been proposed as an underlying mechanism. Importantly, conflicting data exist in the field and both excessive and insufficient mitochondrial fission were proposed to contribute to sarcopenia. In D. Melanogaster, enhancing mitochondrial fission in midlife through overexpression of dynamin-1-like protein (Drp1) extended lifespan and attenuated several key hallmarks of muscle aging. Whether a similar outcome of Drp1 overexpression is observed in mammalian muscles remains unknown. In this study, we investigated the impact of knocking down and overexpressing Drp1 protein for 4 months in skeletal muscles of late middle-aged (18 months) mice using intra-muscular injections of adeno-associated viruses expressing shRNA targeting Drp1 or full Drp1 cDNA. We report that knocking down Drp1 expression late in life triggers severe muscle atrophy, mitochondrial dysfunctions, degeneration/regeneration, oxidative stress and impaired autophagy. Drp1 overexpression late in life triggered mild muscle atrophy and decreased mitochondrial quality. Taken altogether, our results indicate that both overexpression or silencing Drp1 in late middle-aged mice negatively impact skeletal muscle mass and mitochondrial health. These data suggest that Drp1 content must remain within a narrow physiological range to preserve muscle and mitochondrial integrity during aging. Altering Drp1 expression is therefore unlikely to be a viable target to counter sarcopenia. This article is protected by copyright. All rights reserved.

Keywords:  autophagy; mitochondrial dynamics; mitochondrial fission; myopathic phenotype; oxidative stress; skeletal muscle aging; skeletal muscle atrophy

DOI:  https://doi.org/10.1113/JP281752