Journal Article

Skeletal muscle alterations in tachycardia-induced heart failure are linked to deficient natriuretic peptide signalling and are attenuated by RAS-/NEP-inhibition

Bruckmann, Astrid, Schröder, Josef A., Maier, Lars S., Paulus, Michael, Winkel, Ingrid, Luchner, Andreas, Dietl, Alexander, Sossalla, Samuel, Birner, Christoph, Pietrzyk, Gabriela

2019

Overview

Heart failure induced cachexia is highly prevalent. Insights into disease progression are lacking. Early state of left ventricular dysfunction (ELVD) and symptomatic systolic heart failure (HF) were both induced in rabbits by tachypacing. Tissue of limb muscle (LM) was subjected to histologic assessment. For unbiased characterisation of early and late myopathy, a proteomic approach followed by computational pathway-analyses was performed and combined with pathway-focused gene expression analyses. Specimen of thoracic diaphragm (TD) served as control for inactivity-induced skeletal muscle alterations. In a subsequent study, inhibition of the renin-angiotensin-system and neprilysin (RAS-/NEP) was compared to placebo. HF was accompanied by loss of protein content (8.7±0.4% vs. 7.0±0.5%, mean±SEM, control vs. HF, p<0.01) and a slow-to-fast fibre type switch, establishing hallmarks of cachexia. In ELVD, the enzymatic set-up of LM and TD shifted to a catabolic state. A disturbed malate-aspartate shuttle went well with increased enzymes of glycolysis, forming the enzymatic basis for enforced anoxic energy regeneration. The histological findings and the pathway analysis of metabolic results drew the picture of suppressed PGC-1α signalling, linked to the natriuretic peptide system. In HF, natriuretic peptide signalling was desensitised, as confirmed by an increase in the ratio of serum BNP to tissue cGMP (57.0±18.6pg/ml/nM/ml vs. 165.8±16.76pg/ml/nM/ml, p<0.05) and a reduced expression of natriuretic peptide receptor-A. In HF, combined RAS-/NEP-inhibition prevented from loss in protein content (8.7±0.3% vs. 6.0±0.6% vs. 8.3±0.9%, Baseline vs. HF-Placebo vs. HF-RAS/NEP, p<0.05 Baseline vs. HF-Placebo, p = 0.7 Baseline vs. HF-RAS/NEP). Tachypacing-induced heart failure entails a generalised myopathy, preceding systolic dysfunction. The characterisation of \"pre-cachectic\" state and its progression is feasible. Early enzymatic alterations of LM depict a catabolic state, rendering LM prone to futile substrate metabolism. A combined RAS-/NEP-inhibition ameliorates cardiac-induced myopathy independent of systolic function, which could be linked to stabilised natriuretic peptide/cGMP/PGC-1α signalling.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Angiotensin / Angiotensins / Animals / Aspartate / Biochemistry / Biological Transport / Biology and Life Sciences / Biomarkers / Cachexia / Cardiac arrhythmia / Computer applications / Congestive heart failure / Cyclic GMP / Diaphragm / Diaphragm (anatomy) / Disease Models, Animal / Echocardiography / Enzymes / Exercise / Gene expression / Gene Expression Profiling - methods / Genes / Genetic research / Glucose metabolism / Glycolysis / Heart / Heart failure / Heart Failure - diagnosis / Heart Failure - etiology / Heart Failure - metabolism / Hospitals / Hypotheses / Internal medicine / Malate / Medicine / Medicine and Health Sciences / Metabolism / Mitochondria, Muscle - genetics / Mitochondria, Muscle - metabolism / Muscle, Skeletal - metabolism / Muscle, Skeletal - pathology / Muscle, Skeletal - ultrastructure / Muscles / Musculoskeletal system / Myopathy / Natriuretic peptides / Natriuretic Peptides - genetics / Natriuretic Peptides - metabolism / Neprilysin / Omapatrilat / Peptides / Physical fitness / Physiological aspects / Proteins / Proteomics - methods / Rabbits / ras Proteins - antagonists & inhibitors / ras Proteins - metabolism / Regeneration / Renin / Research and Analysis Methods / Signal Transduction / Signaling / Skeletal muscle / Substrate inhibition / Tachycardia / Tachycardia - complications / Tachycardia - diagnosis / Thorax / Ventricle