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

Autoři: Alexander Dietl aff001;  Ingrid Winkel aff002;  Gabriela Pietrzyk aff001;  Michael Paulus aff001;  Astrid Bruckmann aff003;  Josef A. Schröder aff004;  Samuel Sossalla aff001;  Andreas Luchner aff001;  Lars S. Maier aff001;  Christoph Birner aff001
Působiště autorů: Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany aff001;  Institute of Pathology, University of Regensburg, Regensburg, Germany aff002;  Department of Biochemistry I, University of Regensburg, Regensburg, Germany aff003;  Electron Microscopy Core Facility (Emeritus), Institute for Pathology, University Hospital Regensburg, Regensburg, Germany aff004;  Klinik fuer Kardiologie, Krankenhaus der Barmherzigen Brueder, Regensburg, Germany aff005;  Department of Internal Medicine I, Klinikum St. Marien, Amberg, Germany aff006
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article



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.

Klíčová slova:

Cytosol – Enzyme metabolism – Heart failure – Mitochondria – Rabbits – Signal peptides – Skeletal muscles – Natriuretic peptide


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