Molecular Mechanisms of Diaphragm Myopathy in Humans With Severe Heart Failure
- 19 March 2021
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation Research
- Vol. 128 (6), 706-719
- https://doi.org/10.1161/circresaha.120.318060
Abstract
Rationale: Diaphragm weakness impairs quality-of-life, exercise capacity, and survival in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction. However, the underlying cellular mechanisms responsible in humans remain poorly resolved. Objective: We prospectively evaluated clinical, functional (in vivo/in vitro), histological/ultrastructural and molecular alterations of the diaphragm from CHF patients receiving a left ventricular assist device compared to patients without CHF undergoing elective coronary bypass grafting (control) in the observational LIpsia DiaPhrAgm and MUScle Heart Failure Trial (LIPAMUS-HF). Methods and Results: Participants (Controls=21, CHF=18) underwent cardiopulmonary exercise and spirometry/respiratory muscle testing alongside diaphragm and cardiac imaging. Diaphragm biopsies were phenotyped for mitochondrial respiration, muscle fiber function, histology/ultrastructure, and protein expression. In vivo respiratory muscle function and diaphragm thickness were reduced in CHF by 38% and 23%. Diaphragm biopsies revealed a fiber-type shift and severe fiber atrophy in CHF alongside elevated proteasome-dependent proteolysis (i.e., MuRF1 expression, ubiquitination, ubiquitin proteasome activity) and myofibrillar protein oxidation, which corresponded to upregulated NADPH oxidase (Nox2/Nox4) signaling. Mitochondria demonstrated severe intrinsic functional and ultrastructural abnormalities in CHF characterized by accumulation of small mitochondria and inhibited autophagy/mitophagy. Single muscle fiber contractile function revealed reduced Ca2+ sensitivity in CHF and there was evidence of ryanodine receptor 1 (RyR1) dysfunction indicating Ca2+ leak from the sarcoplasmatic reticulum. Mitochondrial and Ca2+ measures corresponded to upregulated Nox4 isoform NADPH oxidase expression. Molecular markers correlated to whole-body exercise intolerance and diaphragm dysfunction/wasting. Conclusions: CHF patients demonstrate an obvious diaphragm myopathy independent of disuse or other confounding factors such as ageing, obesity, or hypertension. Diaphragm weakness in CHF was associated with intracellular abnormalities characterized by fiber atrophy, oxidative stress, mitochondrial dysfunction, impaired Ca2+ homeostasis, elevated proteasome dependent proteolysis, but inhibited autophagy/mitophagy, which we speculate offers a novel therapeutic molecular target regulated by a Nox-MuRF1/ubiquitin proteasome-mitochondria-RyR1/Ca2+ signaling axis.Keywords
Funding Information
- Leipzig Heart Institute (HRC060453)
This publication has 61 references indexed in Scilit:
- Exercise Training Prevents TNF-α Induced Loss of Force in the Diaphragm of MicePLOS ONE, 2013
- Respiratory muscle dysfunction in congestive heart failure—The role of pulmonary hypertensionInternational Journal of Cardiology, 2011
- Assessing mitochondrial dysfunction in cellsBiochemical Journal, 2011
- NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heartProceedings of the National Academy of Sciences of the United States of America, 2010
- Autophagy Is Required to Maintain Muscle MassCell Metabolism, 2009
- Diabetic cardiomyopathy-associated dysfunction in spatially distinct mitochondrial subpopulationsAmerican Journal of Physiology-Heart and Circulatory Physiology, 2009
- Upregulation of uncoupling protein-3 in skeletal muscle during exercise: a potential antioxidant functionFree Radical Biology & Medicine, 2009
- Proteasome inhibition improves diaphragm function in congestive heart failure ratsAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2008
- The initiation factor eIF3-f is a major target for Atrogin1/MAFbx function in skeletal muscle atrophyThe EMBO Journal, 2008
- Stressed out: the skeletal muscle ryanodine receptor as a target of stressJCI Insight, 2008