Differential effects of heart failure with reduced ejection fraction on locomotor and respiratory muscles

Abstract Background Muscle weakness impairs quality-of-life, exercise capacity, and survival in patients with heart failure and reduced left ventricular ejection fraction (HFrEF). However, the effects on systemic concentrations and local expression of inflammatory cytokines and myokines as well as metabolic markers might differ between locomotor and respiratory muscles. Purpose We prospectively evaluated clinical, functional, and molecular alterations of the diaphragm and the M. vastus lateralis (MVL) from HFrEF patients receiving a left ventricular assist device compared to patients without heart failure undergoing elective coronary bypass grafting (control). Methods Participants (Controls=21, HFrEF=18) underwent cardiopulmonary exercise and respiratory and leg muscle testing. Serum concentrations and local expression of inflammatory cytokines and myokines as well as key enzymes of metabolic pathways were examined in biopsies of the diaphragm and MVL. Results Exercise capacity, respiratory muscle function and endurance force of locomotor muscles were significantly reduced in HFrEF compared with controls (all p<0.05). The serum concentration of Il-6, Il-1beta and TNF-alpha were significantly higher or solely detectable in HFrEF compared with controls. Local mRNA expression of Il-6 was not different in MVL but 2.2-fold higher in the diaphragm of HFrEF compared with controls (p=0.013). In contrast, mRNA expression of Il-6 receptor was significantly reduced by 38% (p=0.004) in MVL of HFrEF compared with controls but comparable in the diaphragm. Serum concentrations of FGF-21 and Musclin were significantly higher in HFrEF compared with controls (all p<0.05). Local mRNA expression of FGF-21 was significantly lower in both MVL and diaphragm of HFrEF compared with controls. FGF-21 receptor 1 mRNA expression was reduced by 18% in the MVL of HFrEF (p=0.02), whereas co-receptor klotho was comparable to controls. In the diaphragm, FGF-21 receptor 1 mRNA expression was comparable between HFrEF and controls, but the co-receptor klotho had a 5-fold higher mRNA expression in HFrEF (p=0.002). We examined the activity of key enzymes of glucose, lipid and ketone metabolism as well as key enzymes of the Krebs cycle. The main differences were found for ß-hydroxyacyl-CoA Dehydrogenase in the diaphragm with a 1.6-fold higher activity in HFrEF compared with controls (p=0.01) and for succinyl-CoA: 3-ketoacid-coenzyme A transferase in the MVL with a 2-fold higher activity in HFrEF compared with controls (p<0.01) indicating a main utilization of lipids in the diaphragm and of ketones in the MVL for energy supply. Conclusions HFrEF induced divergent effects on inflammatory markers, myokine expression and metabolic parameters in locomotor and respiratory muscles in HFrEF patients compared with controls. This indicates that different molecular alterations contribute to locomotor/respiratory muscle dysfunction and reduced whole-body exercise capacity.