Exercise Training Prevents Diaphragm Contractile Dysfunction in Heart Failure.
Patient studies have demonstrated the efficacy of exercise training in attenuating respiratory muscle weakness in chronic heart failure (HF), yet direct assessment of muscle fiber contractile function together with data on the underlying intracellular mechanisms remains elusive. The present study, therefore, used a mouse model of HF to assess whether exercise training could prevent diaphragm contractile fiber dysfunction by potentially mediating the complex interplay between intracellular oxidative stress and proteolysis.



Mice underwent sham operation (n = 10) or a ligation of the left coronary artery and were randomized to sedentary HF (n = 10) or HF with aerobic exercise training (HF + AET; n = 10). Ten weeks later, echocardiography and histological analyses confirmed HF.



In vitro diaphragm fiber bundles demonstrated contractile dysfunction in sedentary HF compared with sham mice that was prevented by AET, with maximal force 21.0 ± 0.7 versus 26.7 ± 1.4 and 25.4 ± 1.4 N·cm, respectively (P < 0.05). Xanthine oxidase enzyme activity and MuRF1 protein expression, markers of oxidative stress and protein degradation, were ~20% and ~70% higher in sedentary HF compared with sham mice (P < 0.05) but were not different when compared with the HF + AET group. Oxidative modifications to numerous contractile proteins (i.e., actin and creatine kinase) and markers of proteolysis (i.e., proteasome and calpain activity) were elevated in sedentary HF compared with HF + AET mice (P < 0.05); however, these indices were not significantly different between sedentary HF and sham mice. Antioxidative enzyme activities were also not different between groups.



Our findings demonstrate that AET can protect against diaphragm contractile fiber dysfunction induced by HF, but it remains unclear whether alterations in oxidative stress and/or protein degradation are primarily responsible.
1Department of Internal Medicine and Cardiology, Leipzig University-Heart Center, Leipzig, GERMANY; 2Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, GERMANY; 3Department of Cardiac Surgery, Leipzig University-Heart Center, Leipzig, GERMANY; and 4Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, GERMANY.
Norman
N
Mangner
T Scott
TS
Bowen
Sarah
S
Werner
Tina
T
Fischer
Yvonne
Y
Kullnick
Andreas
A
Oberbach
Axel
A
Linke
Leif
L
Steil
Gerhard
G
Schuler
Volker
V
Adams
D000818:Animals; D003285:Contractile Proteins / Q000378:metabolism; D003964:Diaphragm / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000502:physiology; D009124:Muscle Proteins / Q000378:metabolism; D018384:Oxidative Stress; D010805:Physical Conditioning, Animal; D059748:Proteolysis; D011897:Random Allocation; D000070584:Tripartite Motif Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D003285:Contractile Proteins; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D014969:Xanthine Oxidase; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases