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. 2021 Aug;8(4):2556-2568.
doi: 10.1002/ehf2.13405. Epub 2021 May 5.

Ubiquitin-proteasome-system and enzymes of energy metabolism in skeletal muscle of patients with HFpEF and HFrEF

Volker Adams  1   2 , Sebastian Wunderlich  3 , Norman Mangner  1 , Jennifer Hommel  1 , Katrin Esefeld  4   5 , Stephan Gielen  6 , Martin Halle  4   5 , Øyvind Ellingsen  7   8 , Emeline M Van Craenenbroeck  9   10 , Ulrik Wisløff  8 , Burkert Pieske  11 , Axel Linke  1   2 , Ephraim B Winzer  1
Affiliations

Ubiquitin-proteasome-system and enzymes of energy metabolism in skeletal muscle of patients with HFpEF and HFrEF

Volker Adams et al. ESC Heart Fail. 2021 Aug.

Abstract

Background: Skeletal muscle (SM) alterations contribute to exercise intolerance in heart failure patients with preserved (HFpEF) or reduced (HFrEF) left ventricular ejection fraction (LVEF). Protein degradation via the ubiquitin-proteasome-system (UPS), nuclear apoptosis, and reduced mitochondrial energy supply is associated with SM weakness in HFrEF. These mechanisms are incompletely studied in HFpEF, and a direct comparison between these groups is missing.

Methods and results: Patients with HFpEF (LVEF ≥ 50%, septal E/e' > 15 or >8 and NT-proBNP > 220 pg/mL, n = 20), HFrEF (LVEF ≤ 35%, n = 20) and sedentary control subjects (Con, n = 12) were studied. Inflammatory markers were measured in serum, and markers of the UPS, nuclear apoptosis, and energy metabolism were determined in percutaneous SM biopsies. Both HFpEF and HFrEF showed increased proteolysis (MuRF-1 protein expression, ubiquitination, and proteasome activity) with proteasome activity significantly related to interleukin-6. Proteolysis was more pronounced in patients with lower exercise capacity as indicated by peak oxygen uptake in per cent predicted below the median. Markers of apoptosis did not differ between groups. Mitochondrial energy supply was reduced in HFpEF and HFrEF (complex-I activity: -31% and -53%; malate dehydrogenase activity: -20% and -29%; both P < 0.05 vs. Con). In contrast, short-term energy supply via creatine kinase was increased in HFpEF but decreased in HFrEF (47% and -45%; P < 0.05 vs. Con).

Conclusions: Similarly to HFrEF, skeletal muscle in HFpEF is characterized by increased proteolysis linked to systemic inflammation and reduced exercise capacity. Energy metabolism is disturbed in both groups; however, its regulation seems to be severity-dependent.

Keywords: Atrophy; Diastolic heart failure; Heart failure; Mitochondria; Skeletal muscle exercise; Ubiquitin-proteasome system genetics.

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Conflict of interest statement

Ephraim Winzer reports personal fees from Boehringer‐Ingelheim, Novartis, and CVRx outside of this study. Norman Mangner reports personal fees from Edwards LifeScience, Medtronic, Biotronik, Novartis, Sanofi Genzyme, and AstraZeneca outside the submitted work. Stephan Gielen reports personal fees from Amgen, AstraZeneca, Novartis, Daiichi‐Sankyo, and Sanofi‐Aventis outside and without relevance to the submitted work. Volker Adams, Sebastian Wunderlich, Jennifer Hommel, Katrin Esefeld, Martin Halle, Øyvind Ellingsen, Emeline M. Van Craenenbroeck, Ulrik Wisløff, Burkert Pieskem and Axel Linke declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
The protein expression of MuRF‐1 (A), MAFbx (B), and ubiquitinated proteins (UB‐K48) (C), and the activity of the proteasome (D) was measured in skeletal muscle specimens of control subjects (Control) and patients with heart failure with preserved (HFpEF) or reduced left ventricular ejection fraction (HFrEF). For protein expression, representative western blots and quantitative analysis are shown. Values are shown as means ± SEM.
Figure 2
Figure 2
The protein expression of BCL2 (A) and caspase‐3 (B) was measured in skeletal muscle specimens of control subjects (Control) and patients with heart failure with preserved (HFpEF) or reduced left ventricular ejection fraction (HFrEF). For protein expression, representative western blots and quantitative analysis are shown. Values are shown as means ± SEM.
Figure 3
Figure 3
The enzyme activity of complex‐I (A), complex‐II (succinat dehydrogenase) (B), malate dehydrogenase (C), and creatine kinase (D) was determined in skeletal muscle homogenates from control subjects (Control) and patients with heart failure with preserved (HFpEF) or reduced left ventricular ejection fraction (HFrEF). In addition, protein expression of complex‐II (E) and complex‐V (F) was quantified by western blot analysis. Representative blots are depicted above the respective bar graph. Values are shown as means ± SEM.
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