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Abstract
Pulmonary arterial hypertension (PAH) is characterized by remodelling of the pulmonary arteries and right ventricle (RV), which leads to functional decline of cardiac and skeletal muscle. This study investigated the effects of a multi-targeted nutritional intervention with extra protein, leucine, fish oil and oligosaccharides on cardiac and skeletal muscle in PAH. PAH was induced in female C57BL/6 mice by weekly injections of monocrotaline (MCT) for 8 weeks. Control diet (sham and MCT group) and isocaloric nutritional intervention (MCT + NI) were administered. Compared to sham, MCT mice increased heart weight by 7%, RV thickness by 13% and fibrosis by 60% (all p < 0.05) and these were attenuated in MCT + NI mice. Microarray and qRT-PCR analysis of RV confirmed effects on fibrotic pathways. Skeletal muscle fiber atrophy was induced (P < 0.05) by 22% in MCT compared to sham mice, but prevented in MCT + NI group. Our findings show that a multi-targeted nutritional intervention attenuated detrimental alterations to both cardiac and skeletal muscle in a mouse model of PAH, which provides directions for future therapeutic strategies targeting functional decline of both tissues.
Highlights
Pulmonary hypertension (PH) is a syndrome that can result from different pathological changes in the pulmonary vasculature
Given the adverse effects associated with Pulmonary arterial hypertension (PAH) on multiple-organs, and the underlying role of chronic inflammation in this process, the present study aimed to test whether an anti-inflammatory nutritional intervention high in protein, fish oil and oligosaccharides could attenuate both cardiac and skeletal muscle remodelling in PAH
The change in body weight was not due to a lower food intake in the MCT group compared to the sham group, as cumulative food intake of the mice was identical at the end of the intervention
Summary
Pulmonary hypertension (PH) is a syndrome that can result from different pathological changes in the pulmonary vasculature. Nutritional intervention with high protein, leucine, fish oil and oligosaccharides has been shown to have beneficial effects on skeletal muscle atrophy in a mouse model of cancer[11] This provides evidence of a potential multi-organ treatment for PAH, where both cardiac and skeletal muscle impairments can be targeted in combination. The three known pathways involved in the development of PAH currently targeted by drugs[1] include the endothelin, nitric oxide and prostacyclin pathways[12] While these drugs reduce pulmonary vascular resistance and improve survival, they do not always improve symptoms or address extra-cardiac maladaptations[4]. Given the adverse effects associated with PAH on multiple-organs, and the underlying role of chronic inflammation in this process, the present study aimed to test whether an anti-inflammatory nutritional intervention high in protein, fish oil and oligosaccharides could attenuate both cardiac and skeletal muscle remodelling in PAH. We induced PAH by injection of monocrotaline (MCT) for 8 weeks (a validated animal model for PAH15,16) in female mice to account for the current sex-dependent incidence rate of PAH in humans
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