Abstract 1331 Skeletal muscle iron deficiency worsens cardiac dysfunction and mortality after transverse aortic constriction

Heart failure (HF) often leads to systemic iron deficiency (ID) with or without anemia. HF also promotes skeletal muscle ID, which may result in myopathy and exercise intolerance. We investigated whether skeletal muscle ID, in turn, affects the failing heart. To induce skeletal muscle-specific ID, we crossed iron-regulatory protein (Irp) 1 and 2-floxed mice (Irp^f/f) with mice expressing Cre recombinase specifically in skeletal muscle under the control of the myosin light chain promoter 1 (Cre-Irp1/2^f/f).

Cre-Irp1/2^f/f mice developed skeletal muscle-selective ID with preserved cardiac and systemic iron status and no anemia. At baseline, cardiac (left ventricular) morphology and function were unaltered in Cre-Irp1/2^f/f mice compared with Irp1/2^f/f control mice. At the age of 8–10 weeks, Cre-Irp1/2^f/f and Irp1/2^f/f mice were subjected to sham or transverse aortic constriction (TAC) surgery. Doppler measurements confirmed comparable peak pressure gradients at the site of ligation in both genotypes (41±4 vs. 42±3 mmHg).

Cre-Irp1/2^f/f mice displayed a significantly higher mortality rate after TAC compared to control mice (Figure). No animal died after sham operation. As shown by left ventricular (LV) pressure-volume (PV) loop catheterization, LV ejection fraction (45±3% vs. 58±4%, P=0.02), cardiac output (10±0 vs. 14±1 mL/min, P=0.001), and LV contractility (dP/dtmax, 7412 ± 638 vs. 11498±605 mmHg/s, P<0.001) were reduced in Cre-Irp1/2^f/f mice as early as 1 day after TAC compared with Irp1/2^f/f mice. The number of TUNEL+ cells was increased in left ventricles from TAC-challenged Cre-Irp1/2^f/f mice (1.3±0.1% vs. 0.6±0.1% in Irp1/2^f/f, P=0.002) with greater caspase 3 protein expression (133±4% vs. Irp1/2^f/f, P=0.03). Seven days after TAC, Cre-Irp1/2^f/f mice had developed greater cardiomyocyte hypertrophy (cross sectional area, 112±4% vs. Irp1/2^f/f, P=0.03) and displayed more interstitial left ventricular fibrosis (201±32% vs. Irp1/2^f/f, P=0.03). To start investigating the underlying mechanism(s), we performed transcriptome analyses of LV myocardium from TAC-challenged Cre-Irp1/2^f/f and Irp1/2^f/f mice. Based on Gene Ontology (GO) annotations, several biological processes associated with metabolic function were significantly down-regulated in Cre-Irp1/2^f/f mice.

In conclusion, skeletal muscle-selective ID impairs cardiac adaptation to pressure overload, suggesting a previously unknown cross-talk between iron-deficient skeletal muscle and the myocardium.

Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5
Skeletal muscle iron deficiency worsens cardiac dysfunction and mortality after transverse aortic constriction
Z. Malik¹, B. M. Chung¹, Y. Wang¹, F. Rostami¹, C. Werlein², D. Jonigk³, J. Bauersachs⁴, K. C. Wollert⁴, T. Kempf⁴
¹Molekulare und Translationale Kardiologie, Medizinische Hochschule Hannover, Hannover; ²Institut für Pathologie, Medizinische Hochschule Hannover, Hannover; ³Standort Hannover "Breath", Deutsches Lungenzentrum, Hannover; ⁴Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover;
Heart failure (HF) often leads to systemic iron deficiency (ID) with or without anemia. HF also promotes skeletal muscle ID, which may result in myopathy and exercise intolerance. We investigated whether skeletal muscle ID, in turn, affects the failing heart. To induce skeletal muscle-specific ID, we crossed iron-regulatory protein (Irp) 1 and 2-floxed mice (Irp^f/f) with mice expressing Cre recombinase specifically in skeletal muscle under the control of the myosin light chain promoter 1 (Cre-Irp1/2^f/f). Cre-Irp1/2^f/f mice developed skeletal muscle-selective ID with preserved cardiac and systemic iron status and no anemia. At baseline, cardiac (left ventricular) morphology and function were unaltered in Cre-Irp1/2^f/f mice compared with Irp1/2^f/f control mice. At the age of 8–10 weeks, Cre-Irp1/2^f/f and Irp1/2^f/f mice were subjected to sham or transverse aortic constriction (TAC) surgery. Doppler measurements confirmed comparable peak pressure gradients at the site of ligation in both genotypes (41±4 vs. 42±3 mmHg). Cre-Irp1/2^f/f mice displayed a significantly higher mortality rate after TAC compared to control mice (Figure). No animal died after sham operation. As shown by left ventricular (LV) pressure-volume (PV) loop catheterization, LV ejection fraction (45±3% vs. 58±4%, P=0.02), cardiac output (10±0 vs. 14±1 mL/min, P=0.001), and LV contractility (dP/dtmax, 7412 ± 638 vs. 11498±605 mmHg/s, P<0.001) were reduced in Cre-Irp1/2^f/f mice as early as 1 day after TAC compared with Irp1/2^f/f mice. The number of TUNEL+ cells was increased in left ventricles from TAC-challenged Cre-Irp1/2^f/f mice (1.3±0.1% vs. 0.6±0.1% in Irp1/2^f/f, P=0.002) with greater caspase 3 protein expression (133±4% vs. Irp1/2^f/f, P=0.03). Seven days after TAC, Cre-Irp1/2^f/f mice had developed greater cardiomyocyte hypertrophy (cross sectional area, 112±4% vs. Irp1/2^f/f, P=0.03) and displayed more interstitial left ventricular fibrosis (201±32% vs. Irp1/2^f/f, P=0.03). To start investigating the underlying mechanism(s), we performed transcriptome analyses of LV myocardium from TAC-challenged Cre-Irp1/2^f/f and Irp1/2^f/f mice. Based on Gene Ontology (GO) annotations, several biological processes associated with metabolic function were significantly down-regulated in Cre-Irp1/2^f/f mice. In conclusion, skeletal muscle-selective ID impairs cardiac adaptation to pressure overload, suggesting a previously unknown cross-talk between iron-deficient skeletal muscle and the myocardium.
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