Reduced aerobic capacity causes leaky ryanodine receptors that trigger arrhythmia in a rat strain artificially selected and bred for low aerobic running capacity

Høydal, Morten A.; Stølen, Tomas; Johnsen, Anne Berit; Alvez, Marcia; Catalucci, Daniele; Condorelli, Gianluigi; Koch, Lauren G.; Britton, Steven L.; Smith, Godfrey L.; Wisløff, Ulrik

doi:10.1111/apha.12238

Cited by 9 publications

(13 citation statements)

References 44 publications

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“…In fact, inactivity is linked to increased morbidity and mortality due to chronic pathologies (2,43). Interestingly, the muscle transcriptome of LCRs associates with biological functions related to cardiovascular disease, further reflecting their poor health condition as previously documented (28,(44)(45)(46)(47)(48). Remarkably, the same analysis also pointed out a curious association to morbidity/mortality.…”

Section: Discussionsupporting

confidence: 59%

Comparative Analysis of Skeletal Muscle Transcriptional Signatures Associated With Aerobic Exercise Capacity or Response to Training in Humans and Rats

et al. 2020

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Increasing exercise capacity promotes healthy aging and is strongly associated with lower mortality rates. In this study, we analyzed skeletal muscle transcriptomics coupled to exercise performance in humans and rats to dissect the inherent and response components of aerobic exercise capacity. Using rat models selected for intrinsic and acquired aerobic capacity, we determined that the high aerobic capacity muscle transcriptome is associated with pathways for tissue oxygenation and vascularization. Conversely, the low capacity muscle transcriptome indicated immune response and metabolic dysfunction. Low response to training was associated with an inflammatory signature and revealed a potential link to circadian rhythm. Next, we applied bioinformatics tools to predict potential secreted factors (myokines). The predicted secretome profile for exercise capacity highlighted circulatory factors involved in lipid metabolism and the exercise response secretome was associated with extracellular matrix remodelling. Lastly, we utilized human muscle mitochondrial respiration and transcriptomics data to explore molecular mediators of exercise capacity and response across species. Human transcriptome comparison highlighted epigenetic mechanisms linked to exercise capacity and the damage repair for response. Overall, our findings from this crossspecies transcriptome analysis of exercise capacity and response establish a foundation for future studies on the mechanisms that link exercise and health.

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Section: Discussionsupporting

confidence: 59%

Comparative Analysis of Skeletal Muscle Transcriptional Signatures Associated With Aerobic Exercise Capacity or Response to Training in Humans and Rats

et al. 2020

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“…We have previously published an account of segregation observed in the same parameters as in the current study, in comparable generations of the LCR–HCR model system: previously in generations 14, 15, 17, 21, 14 and 22, 18 as well as in generation 16 in the current study. The overlap between generations renders compatibility between studies.…”

Section: Discussionsupporting

confidence: 65%

“…In particular, the cardiometabolic health indices differ widely between LCRs and HCRs, to the degree that while HCRs develop an athletic phenotype, LCRs resemble a metabolic syndrome phenotype and show signs of mild cardiac pathology, as evidenced by visceral obesity, insulin resistance, elevated triglycerides, dyslipidemia, hypertension, reduced heart function, and development of mild concentric myocardial hypertrophy. 10,14,17,18 These LCR-HCR differences are inborn and not caused by experimental genetic manipulation or other interventions such as exercise training, 7,8 albeit they may affect the outcome of exercise training interventions. 29 Thus, the phenotypic differences between LCRs and HCRs have evolved and enriched over time due to continued selective breeding over many generations and are, therefore, genetic in origin, and as such, create a useful model to investigate intrinsic characteristics in widely different genetic backgrounds.…”

Section: Introductionmentioning

confidence: 99%

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Inherited physical capacity: Widening divergence from young to adult to old

Kemi,

Hoydal,

Haram

et al. 2024

Annals of the New York Academy of Sciences

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Cardiorespiratory performance segregates into rat strains of inherited low‐ and high‐capacity runners (LCRs and HCRs); during adulthood, this segregation remains stable, but widens in senescence and is followed by segregated function, health, and mortality. However, this segregation has not been investigated prior to adulthood. We, therefore, assessed cardiorespiratory performance and cardiac cell (cardiomyocyte) structure–function in 1‐ and 4‐month‐old LCRs and HCRs. Maximal oxygen uptake was 23% less in LCRs at 1‐month compared to HCRs at 1‐month, and 72% less at 4 months. Cardiomyocyte contractility was 37−56% decreased, and Ca2+ release was 34−62% decreased, in 1‐ and 4‐month LCRs versus HCRs. This occurred because HCRs had improved contractility and Ca2+ release during maturation, whereas LCRs did not. In quiescent cardiomyocytes, LCRs displayed 180% and 297% more Ca2+ sparks and 91% and 38% more Ca2+ waves at 1 and 4 months versus HCRs. Cell sizes were not different between LCRs and HCRs, but LCRs showed reduced transverse‐tubules versus HCRs, though no discrepant transverse‐tubule generation occurred during maturation. In conclusion, LCRs show reduced scores for aerobic capacity and cardiomyocyte structure–function compared to HCRs and there is a widening divergence between LCRs and HCRs during juvenile to near‐adult maturation.

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“…The HCR animals generally are characterized as "disease resistant, " while the LCR animals are characterized as disease prone. Interestingly, the HCR/LCR strains demonstrate many of the same traits related to CVD that had been previously associated with active exercise (48)(49)(50)(51)(52) including some mitochondrial/metabolic effects (53,54). Still, cardioprotection in the HCRs is not always observed (55)(56)(57), and while LCR did associate with a higher incidence of pump failure, it did not associate with multiorgan system failure in hemorrhagic shock (58).…”

Section: Introductionmentioning

confidence: 78%

Augmented Cardiac Mitochondrial Capacity in High Capacity Aerobic Running “Disease-Resistant” Phenotype at Rest Is Lost Following Ischemia Reperfusion

Alsahly

Zakari

Koch

et al. 2021

Front. Cardiovasc. Med.

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Rationale: Regular active exercise is considered therapeutic for cardiovascular disease, in part by increasing mitochondrial respiratory capacity, but a significant amount of exercise capacity is determined genetically. Animal models, demonstrating either high capacity aerobic running (HCR) or low capacity aerobic running (LCR) phenotypes, have been developed to study the intrinsic contribution, with HCR rats subsequently characterized as “disease resistant” and the LCRs as “disease prone.” Enhanced cardioprotection in HCRs has been variable and mutifactoral, but likely includes a metabolic component. These studies were conducted to determine the influence of intrinsic aerobic phenotype on cardiac mitochondrial function before and after ischemia and reperfusion.Methods: A total of 34 HCR and LCR rats were obtained from the parent colony at the University of Toledo, housed under sedentary conditions, and fed normal chow. LCR and HCR animals were randomly assigned to either control or ischemia-reperfusion (IR). On each study day, one HCR/LCR pair was anesthetized, and hearts were rapidly excised. In IR animals, the hearts were immediately flushed with iced hyperkalemic, hyperosmotic, cardioplegia solution, and subjected to global hypothermic ischemic arrest (80 min). Following the arrest, the hearts underwent warm reperfusion (120 min) using a Langendorff perfusion system. Following reperfusion, the heart was weighed and the left ventricle (LV) was isolated. A midventricular ring was obtained to estimate infarction size [triphenyltetrazolium chloride (TTC)] and part of the remaining tissue (~150 mg) was transferred to a homogenation buffer on ice. Isolated mitochondria (MITO) samples were prepared and used to determine respiratory capacity under different metabolic conditions. In control animals, MITO were obtained and prepared similarly immediately following anesthesia and heart removal, but without IR.Results: In the control rats, both resting and maximally stimulated respiratory rates were higher (32 and 40%, respectively; p < 0.05) in HCR mitochondria compared to LCR. After IR, resting MITO respiratory rates were decreased to about 10% of control in both strains, and the augmented capacity in HCRs was absent. Maximally stimulated rates also were decreased more than 50% from control and were no longer different between phenotypes. Ca++ retention capacity and infarct size were not significantly different between HCR and LCR (49.2 ± 5.6 vs. 53.7 ± 4.9%), nor was average coronary flow during reperfusion or arrhythmogenesis. There was a significant loss of mitochondria following IR, which was coupled with decreased function in the remaining mitochondria in both strains.Conclusion: Cardiac mitochondrial capacity from HCR was significantly higher than LCR in the controls under each condition. After IR insult, the cardiac mitochondrial respiratory rates were similar between phenotypes, as was Ca++ retention capacity, infarct size, and arrhythmogenicity, despite the increased mitochondrial capacity in the HCRs before ischemia. Relatively, the loss of respiratory capacity was actually greater in HCR than LCR. These data could suggest limits in the extent to which the HCR phenotype might be “protective” against acute tissue stressors. The extent to which any of these deficits could be “rescued” by adding an active exercise component to the intrinsic phenotype is unknown.

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Reduced aerobic capacity causes leaky ryanodine receptors that trigger arrhythmia in a rat strain artificially selected and bred for low aerobic running capacity

Cited by 9 publications

References 44 publications

Comparative Analysis of Skeletal Muscle Transcriptional Signatures Associated With Aerobic Exercise Capacity or Response to Training in Humans and Rats

Comparative Analysis of Skeletal Muscle Transcriptional Signatures Associated With Aerobic Exercise Capacity or Response to Training in Humans and Rats

Inherited physical capacity: Widening divergence from young to adult to old

Augmented Cardiac Mitochondrial Capacity in High Capacity Aerobic Running “Disease-Resistant” Phenotype at Rest Is Lost Following Ischemia Reperfusion

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