Heart failure is a progressive pathophysiological condition that affects the pumping action of heart muscle1. It affects over 23 million people worldwide, with over 5.8 million in the USA, and around a third of patients die within one year of diagnosis2.
The reduced effectiveness of the heart prevents blood from being circulated at an adequate rate to meet the body's normal metabolic requirements. Patients consequently experience shortness of breath and excessive tiredness, which limits their ability to exercise and undertake routine daily activities, thereby reducing their quality of life.
The imbalance between energy consumption and production leads to impaired energy metabolism, such as adenosine triphosphate (ATP) transfer and utilization, in the heart itself that further exacerbates the problem3. Also, skeletal muscle dysfunction, including impaired contractile function and muscle atrophy, can develop4. Mitochondrial dysfunction is commonly observed in both cardiac and skeletal muscle among patients with heart failure5.
To optimize the management of heart failure and improve patient quality of life, a greater understanding of the link between changes in skeletal muscle metabolism and cardiac muscle metabolism is needed.
Skeletal muscle metabolism
The types of skeletal muscle dysfunction observed in patients with heart failure may be associated with many different pathways6. Skeletal muscle atrophy is closely associated with decreased exercise capacity and can result from an imbalance between protein synthesis and protein degradation, which also regulates amino acid levels in the skeletal muscle. In contrast, mitochondrial dysfunction is more strongly associated with decreased glucose and fatty acid oxidation, which typically arises because of a greater reliance on anaerobic metabolism.
These metabolic and functional changes in skeletal muscle lead to decreased exercise capacity, which can be exacerbated in patients with heart failure by a decline in cardiopulmonary function. It is known that exercise capacity can be improved by exercise training and that this can prevent aging-related cardiac structural modeling whereby reducing the risk of heart failure7,8
Metabolic impact of exercise training in muscle
Exercise training improves energy production which in turn reduces the impact of skeletal muscle abnormalities. It has also been shown to improve cardiac function by reducing the adrenergic response. Available data thus suggest that exercise training has the potential to improve cardiovascular health. Although this would be of great benefit to patients with heart failure and those at high risk of heart failure, little is known about the metabolic profile changes in myocardial muscle and skeletal muscle induced by exercise training.
By detecting metabolites that are involved in the metabolic pathways that are affected by exercise training to provide positive benefits, it may be possible to identify biomarkers or novel treatment options for the management of heart failure.
A recent study determined the metabolic profiles in myocardial heart muscle and skeletal muscle after moderate- and high-intensity exercise training in rats with surgically induced myocardial infarction9. A group of healthy rats was included as a control. In particular, links between exercise-induced metabolic changes occurring in cardiac muscle and skeletal muscle were investigated.
The rats were randomly allocated to exercise training programs of different intensities, which they undertook for 60 minutes per day, five days a week, for six weeks. After the ﬁnal training session, the rats were sacriﬁced and tissues from the myocardial and skeletal muscles were extracted. The tissue extracts were then analyzed by proton magnetic resonance spectroscopy using a fully-automated Bruker Avance III Ultra-shielded Plus 600 MHz spectrometer equipped with a 5 mm QCI Cryoprobe in combination with Bruker’s new ICON™-NMR. Data were interpreted using Bruker TopSpin v3.1 software.
The observed changes differed between the heart muscle and skeletal muscle, and thus different metabolic pathways might be affected. Heart failure was shown to affect the concentrations of multiple metabolites of myocardial metabolism but had little effect on skeletal muscle metabolism. The rats with heart failure had higher glucose, glycine, taurine, aspartate, succinate, and lactate concentration than control rats, but lower levels of creatine, phosphocreatine, glycerophosphocholine, glutamine, glutamate, lysine, acetate, and alanine in the myocardium9. There was no significant difference in skeletal muscle metabolites between rats with heart failure and control rats. However, both myocardial and skeletal muscle had altered amino acid metabolism in patients with heart failure. The specific amino acids type affected were different with glutamine being the main metabolite that changed in heart, whereas it was the lysine level that was most affected in skeletal muscle.
The myocardial metabolic signature was not altered by exercise training. In contrast, exercise training markedly altered the metabolite distribution in skeletal muscle. However, exercise training significantly altered the levels of glycine, taurine, acetate, lysine, alanine, lactate, and anserine in skeletal muscle. Exercise training lowered levels of taurine in the skeletal muscle of control rats whilst lysine was reduced in the skeletal muscle of rats with heart failure.
The latest research findings indicate that the changes in the metabolic profile during heart failure mainly affected the heart, whereas metabolic responses to exercise training mainly affected skeletal muscle. Conversely, heart failure had a limited effect on skeletal muscle metabolism, whereas exercise training had a limited effect on metabolism in the heart. The key metabolites that are disturbed by heart failure are taurine and hypotaurine metabolism in skeletal muscle and carnitine synthesis in myocardial tissue.
- White HD, Chew DP. Acute myocardial infarction. Lancet 2008, 372, 570–584
- James S, et al. Cardiol. 2015;178:268–274. https://www.ncbi.nlm.nih.gov/pubmed/25464268
- Fukushima A, et al. Curr. Pharm. Des. 2015;21:3654–3664.
- Kitzman DW, et al. Am. J. Physiol. Heart Circ. Physiol. 2014;306:H1364–H1370.
- Rosca MG, Hoppel CL. Heart Fail. Rev. 2013;18:607–622.
- Bowen TS, et al. Eur. J. Heart Fail. 2015;17:263–272.
- Hirai DM, et al. Am J Physiol. Heart Circ. Physiol. 2015;309:H1419–H1439. https://www.ncbi.nlm.nih.gov/pubmed/26320036
- Santulli G, et al. Front. Physiol. 2013;4:209. https://www.ncbi.nlm.nih.gov/pubmed/23964243
- Shi M, et al. Metabolites 2019;9:53. doi:10.3390/metabo9030053