Impact of high-intensity exercise training (HIIT) versus moderate continuous training (MCT) on skeletal muscle alterations in HFrEF: a substudy of the SMART-EX trial
Authors: Winzer E B , Augstein A , Maennel A , Lange A , Hommel J , Mangner N , Halle M , Linke A , Adams V 
Published: November 2023

Abstract

Background
Skeletal muscle dysfunction contributes to exercise intolerance in chronic heart failure. The randomized multicenter Study of Myocardial Recovery After Exercise Training in Heart Failure (SMART-EX) has shown that high-intensity exercise training (HIIT) but not moderate continuous training (MCT) reduced the left ventricular end diastolic diameter. Both training modalities significantly increased exercise tolerance as determined by cardiopulmonary exercise testing (CPET). However, the underlying molecular alterations within the skeletal muscle with respect to different exercise training modalities are largely unknown.

Methods
In patients with chronic heart failure with reduced ejection fraction (HFrEF) who participated in the SMART-EX skeletal muscle substudy needle biopsies from the vastus lateralis muscle were performed before and after 12 weeks of supervised HIIT, MCT, or recommendation of regular exercise (RRE) to allow molecular assessment of markers for muscle catabolism, inflammation and energy supply by RT-PCR and western blotting. Echocardiography and CPET were performed in all patients. Changes over time were tested within each group.

Results
Skeletal muscle biopsies at baseline and follow-up were available in 31 patients (HIIT n=9; MCT n=9; RRE n=13). The majority of patients were male (87%). Median left ventricular ejection fraction was 29%. Median improvement in peak VO2 was 2.0 (IQR -0.4-2.8) in HIIT vs. 1.4 (IQR -0.9-3.4) in MCT vs. 0.0 (IQR -2.9-2.1) ml/min/kg in RRE. This was statistically not significant. HIIT reduced mRNA levels of the E3 ligases of the ubiquitine proteasome system MuRF1 by -72% (p&lt;0.01) and MafBx -45% (p=0.09) with no change in MCT (MuRF1 -31%, p=0.23; MafBx -47%, p=0.21) and RRE (MuRF1 -8%, p=0.20; MafBx -6%, p=0.46). There was no change in mRNA expression of the inflammatory markers interleukin 6 (HIIT 12%; MCT 29%; RRE -35%; n.s.) and TNFα (HIIT -9%; MCT 20%; RRE 27%; n.s.) in either group. The mRNA expression of the mitochondrial F1 subunit of complex V (ATP5F1) significantly increased in HIIT by 14% (p&lt;0.05) with no change in MCT (-3%, p=0.75) and RRE (2%, p=0.76). The mRNA expression of mitochondrial complex I subunits NDUFB8 and NDUFB6 remained unchanged in all groups. Western blot analysis of porin expression, which is a marker of total mitochondrial content, revealed a significant increase in HIIT by 69% (p&lt;0.05) whereas MCT (21%, p=0.18) and RRE (4%, p=0.79) remained unchanged.

Conclusion
High-intensity interval training in HFrEF for 12 weeks resulted in reduced markers of protein degradation via the ubiquitine proteasome system and increased markers of mitochondrial content and energy supply via mitochondrial complex V whereas moderate continuous exercise training had only minor (non-significant) effects. These molecular changes are probably one reason why exercise capacity improved in patients of the SMART-EX trail.