eRapport

Trening og energistoffskifte

Prosjekt
Prosjektnummer
47091600
Ansvarlig person
Mingshu Shi
Institusjon
NTNU, ISB
Prosjektkategori
Toppfinansiering
Helsekategori
Cardiovascular
Forskningsaktivitet
4. Detection and Diagnosis
Rapporter
2019 - sluttrapport
-- END REPORT -- BACKGROUND: Heart failure is associated with reduced exercise capacity and impaired myocardial and skeletal muscle metabolism. Other factors, such as inborn genetic difference, ageing, and exercise training, can also lead to different exercise capacity. The purpose of this PhD project was to use magnetic resonance spectroscopy (MRS) to determine metabolic profiles in myocardial and skeletal muscle, associated with heart failure and exercise capacity, and thus identify targets for clinical MRS in vivo. METHODS: Two experimental models in rats were used. Coronary artery ligation was applied to induce heart failure, and low versus high capacity runners (LCR/HCR) were used to mimic individuals with different intrinsic exercise capacity. LCR/HCR rats were divided into 9 and 18 months groups to investigate the effect of ageing. In heart failure, exercise training was performed at moderate and high intensity. In LCR/HCR training intensity was high, whereas frequency was reduced. Magnetic resonance spectra were acquired from myocardial or skeletal muscle extracts. A combination of univariate (t-test and analysis of variance) and multivariate methods (principal component analysis or partial least square discriminative analysis) were used to determine the differences in metabolic profile. RESULTS: Heart failure affected multiple metabolic pathways, including creatine metabolism, glucose metabolism, glutamine metabolism, and aspartate metabolism, whereas it had a limited effect on skeletal muscle metabolism. Exercise training increased adenosine triphosphate and decreased glucose in the myocardium. In addition, it altered the skeletal muscle metabolism by regulating the metabolism of taurine, hypotaurine, and carnitine. In the LCR/HCR model, high intrinsic fitness was associated with higher glutamine and glutamate, as well as lower lactate levels in skeletal muscle. Ageing was associated with increased glycerophosphocholine and glucose levels. Exercise training did not cause any detectable changes on metabolic profile in LCR/HCR. CONCLUSION: MRS spectroscopy identified several myocardial and skeletal muscle metabolic profiles associated with the characteristic changes in cardiac function and aerobic fitness in heart failure, exercise training, ageing and intrinsic running capacity. Although some of them pointed to pathways of putative mechanistic importance, further research is necessary to determine their potential as diagnostic and prognostic biomarkers. BACKGROUND The present PhD project was the first step in an attempt to develop new MR-based medical technology to evaluate the functional state of the heart muscle in patients with heart disease. It applied MR spectroscopy (MRS) analysis of tissue samples from experimental models to investigate whether this approach has the potential to identify changes in relevant metabolic pathways. RESULTS MRS spectroscopy identified several myocardial and skeletal muscle metabolic profiles associated with the characteristic changes in cardiac function and aerobic fitness in heart failure, exercise training, ageing and intrinsic running capacity. • Heart failure affected the myocardial metabolism of creatine, glucose, glutamine and aspartate metabolism, whereas it had a limited effect on skeletal muscle metabolism. • Exercise training increased adenosine triphosphate and decreased glucose in the myocardium. In skeletal muscle, it regulated the metabolism of taurine, hypotaurine, and carnitine. • Ageing was associated with increased glycerophosphocholine and glucose levels. • High intrinsic running capacity was associated with higher glutamine and glutamate, as well as lower lactate levels in skeletal muscle. In general, the metabolic changes in heart failure and ageing pointed towards negative effects on cardiac function, whereas the profiles in exercise training and high intrinsic running capacity were associated with favourable effects. CONCLUSION Although some of the metabolic profiles pointed to pathways of putative mechanistic importance, further research is necessary to determine their potential as diagnostic biomarkers.
2018
Low aerobic exercise capacity is a strong independent predictor of cardiovascular disease and premature death. This study determined metabolic profiles in a rat model of inborn low versus high capacity runners (LCR/HCR) and to determine the effect of inborn aerobic capacity, aging, and exercise training on skeletal muscle metabolic profile.k´To get a better understanding of the interplay between aerobic capacity and skeletal muscle metabolic profile, the effect of aging and low volume exercise training were assessed in the experimental LCR/HCR rat model. We hypothesized that age, intrinsic running capacity, and exercise training would affect skeletal muscle metabolic profile, and that the changes would be related to aerobic energy metabolism and share similarities with the pathogenesis of the metabolic syndrome. A long-term goal was to find a novel method to identify impaired skeletal muscle metabolism by using metabolomics based on magnetic resonance. We found that sedentary HCR rats had 54% and 30% higher VO2max compared to sedentary LCR rats at 9 months and 18 months, respectively. In HCR, exercise increased running speed significantly, and VO2max was higher at age of 9 months, compared to sedentary counterparts. In LCR, changes were small and did not reach the level of significance. The metabolic profile was significantly different in the LCR sedentary group compared to the HCR sedentary group at the age of 9 and 18 months, with higher glutamine and glutamate levels (9 months) and lower lactate level (18 months) in HCR. Irrespective of fitness level, aging was associated with increased soleus muscle concentrations of glycerophosphocholine and glucose. Interval training did not influence metabolic profiles in LCR or HCR rats at any age. In conclusion, differences in inborn aerobic capacity gave the most marked contrasts in metabolic profile, there were also some changes with ageing. Low volume high intensity interval training twice a week had no detectable effect on metabolic profile.
2017
Low aerobic exercise capacity is a strong independent predictor of cardiovascular disease and premature death. This study was to determine the metabolic profiles in a rat model of low capacity runners (LCR) and high capacity runners (HCR) and to investigate the variation with aerobic capacity, aging, and exercise training on muscle metabolism.Recent studies have shown that exercise capacity is an independent predictor of cardiovascular disease and premature death, perhaps stronger than other established risk factors, such as age, smoking, hypercholesterolemia, hypertension, and diabetes. Low exercise capacity can result from both intrinsic factors (e.g., genetics, preterm birth) and from acquired factors (inactivity, unhealthy eating, environmental factors) increasing the risk of metabolic syndromes (e.g., diabetes, obesity, etc.) . Several metabolic pathways, such as glucose utilization, citrate acid cycle, amino acid utilization or lipid metabolism in skeletal muscle, could be linked to exercise capacity, and thus to pathogenic processes . In cardiovascular diseases such as heart failure, several lines of evidence suggest that exercise training benefits these patients physiologically . The benefits of exercise training include improved in myocardial oxidative metabolism, ventricular function, coronary circulation . Exercise capacity and cardiovascular fitness are associated with metabolic reprogramming and enhances the function of skeletal muscle . However, it has not been investigated to what extent the beneficial effects are dependent on characteristics of the individual, such as age and intrinsic capacity for exercise. To get a better understanding of the relationship between skeletal muscle metabolism and exercise capacity related diseases, a rat model of low versus high aerobic capacity runners (LCR/HCR), was applied to investigate energy metabolism in skeletal muscle, as well as the effect of interventions on bioenergetics . By utilizing this model, we hypothesized that age, intrinsic running capacity and exercise training would affect skeletal muscle metabolism. Furthermore, we hypothesized that the altered metabolism, would be related to aerobic energy metabolism and share similarities with the metabolic syndrome pathogenesis as described before . Therefore, we investigated the metabolic profiles in skeletal muscle of LCR and HCR rats by using metabolomics based on magnetic resonance spectroscopy (MRS), and correlated with, whole-body oxygen consumption (VO2max). The result showed that sedentary HCR rats had 54% and 30% higher VO2max compared to sedentary LCR rats at 9-months and 18-months, respectively. In HCR, exercise increased running speed significantly and VO2max was higher in 9-month old exercised for 3 months compared to sedentary counterparts. In LCR, changes were small and did not reach the level of significance. The metabolic profile was significantly different in the LCR sedentary group compared to the HCR sedentary group at the age of 9 and 18 months, with higher glutamine and glutamate levels and lower lactate level in HCR. Irrespective of fitness level, aging was associated with a change in the metabolic profile, especially pronounced with increased concentrations of glycerophosphocholine with age. Exercise training did not influence metabolic profiles in LCR or HCR rats at any age. In conclusion, the metabolic profiles were significantly different between HCR and LCR rats and between 9-month and 18-months rats. Interval training twice a week induced limited effects by only improving VO2max level in 9-month HCR rats and non in metabolic profile.
2016
Heart failure (HF) impairs resting myocardial energetics and exercise training is included in most rehabilitation programs and benefits HF patients. The aim of this study was to investigate the effects of exercise training at different intensities in HF rats.In this study, we firstly used rats underwent myocardial infarctions or sham operations and were separated into three exercise groups: sedentary control, moderate intensity, or high intensity. The impact of HF and exercise training on energy metabolism was evaluated by 31P MRS and mitochondrial respirometry. The concentrations of key bioenergetic metabolites phosphocreatine (PCr), adenosine triphosphate (ATP), and inorganic phosphate (Pi) were quantified by MRS. VO2max was measured by treadmill respirometry. From the methodology, we obtained the data from whole body oxygen consumption test, in vitro MR spectroscopy and in situ mitochondrial function. In summary, our study investigated the effect of different exercise training intensities on energy metabolism in HF. Heart failure induced a significant reduction in PCr/ATP ratio, the clinically examined biomarker of heart failure, in our HF rat models. This reduction was induced by decreased level of PCr with unchanged ATP levels. As we hypothesized, the energy metabolism was impaired in HF rats and could be recovered after exercise training. This is reflected in relatively increased ATP level. Furthermore, the reduced mitochondrial respiratory capacity in HF rats was partially recovered by high-intensity exercise training, through increased complex I respiration. These adaptations were associated with an improvement in VO2max and running capacity. The experimental rat model mimics human physiology and helps us to further understand the mechanism of cardiac performance improvement by exercise training. Taken together, our results show that the repressed PCr levels in MI hearts may not be crucial to exercise adaptation. Exercise training in our HF rat model resulted in significant improvement in exercise capacity, and modulated mitochondrial function, VO2max, and ATP availability through mitochondrial respiration. These findings support the hypothesis that exercise training could have potentially important implications in clinical treatment for patients with HF. Considering the close association between ATP and PCr transfer, the molecular mechanism in which unchanged PCr and increased ATP synthesis could improve energy metabolism post exercise training remains to be investigated.
2015
Information on energy metabolism from magnetic resonance spectroscopy may reveal important details of heart muscle function.The aim of the present project is to determine whether magnetic resonance spectroscopy (MRS) can be used to evaluate the function of the heart muscle. Previous studies have shown that reduced heart muscle function in heart failure is associated with impaired energy metabolism in the heart, and that this can be detected noninvasively by this method. We have already shown that exercise training improves heart muscle function in heart failure. Therefore, the working hypothesis of the present PhD project was that exercise training improves cardiac function and partially restores myocardial energy metabolism. If this is the case, then in vivo MRS could be used as a noninvasive method to evaluate the effects of training and other treatments in heart failure patients. The project started in May 2015, and the first part was to determine the changes in energy metabolism in an experimental model of heart failure and exercise training in rats. Analysis of tissue samples from the heart muscle showed that myocardial infarction and exercise training influenced the level of two high-energy phosphor metabolites (phosphocreatine and adenosine triphosphate). It is likely that these changes resulted from reduced mitochondrial function, which is a central part of energy metabolism. These early results have been reported in a manuscript that has been submitted to the Journal of Applied physiology. The next part of the project will be to test out whether we are able to detect similar changes using noninvasive MRS measurements in the same model. Even if there is still much work to do, the project is proceeding according to plan.
Vitenskapelige artikler
Shi M, Ellingsen Ø, Bathen TF, Høydal MA, Stølen T, Esmaeili M

The Effect of Exercise Training on Myocardial and Skeletal Muscle Metabolism by MR Spectroscopy in Rats with Heart Failure.

Metabolites 2019 Mar 19;9(3). Epub 2019 mar 19

PMID: 30893827 - Inngår i doktorgradsavhandlingen

Stølen T, Shi M, Wohlwend M, Høydal MA, Bathen TF, Ellingsen Ø, Esmaeili M

Effect of exercise training on cardiac metabolism in rats with heart failure.

Scand Cardiovasc J 2020 Apr;54(2):84-91. Epub 2019 sep 10

PMID: 31500456 - Inngår i doktorgradsavhandlingen

Shi M, Ellingsen Ø, Bathen TF, Høydal MA, Koch LG, Britton SL, Wisløff U, Stølen TO, Esmaeili M

Skeletal muscle metabolism in rats with low and high intrinsic aerobic capacity: Effect of aging and exercise training.

PLoS One 2018;13(12):e0208703. Epub 2018 des 11

PMID: 30533031 - Inngår i doktorgradsavhandlingen

Doktorgrader
Mingshu Shi

MRS-based metabolic profiling of cardiac and skeletal muscle from rats with heart failure, ..., aging and exercise training

Disputert:
desember 2019
Hovedveileder:
Øyvind Ellingsen
Deltagere
  • Ulrik Wisløff Prosjektdeltaker
  • Morten Andre Høydal Prosjektdeltaker
  • Mingshu Shi Doktorgradsstipendiat
  • Øyvind Ellingsen Hovedveileder
  • Tomas Stølen Medveileder, biveileder
  • Tone Frost Bathen Hovedveileder
  • Morteza Esmaeili Medveileder, biveileder
  • Morteza Esmaeili Prosjektdeltaker
  • Øyvind Ellingsen Prosjektleder
  • Mingshu Shi Doktorgradsstipendiat

eRapport er utarbeidet av Sølvi Lerfald og Reidar Thorstensen, Regionalt kompetansesenter for klinisk forskning, Helse Vest RHF, og videreutvikles av de fire RHF-ene i fellesskap, med støtte fra Helse Vest IKT

Alle henvendelser rettes til Helse Midt-Norge RHF - Samarbeidsorganet og FFU

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