Background: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease predominantly affecting women and characterized by right ventricular (RV) remodeling. PAH patients experience exercise intolerance and fatigue, often associated with functional decline of their cardiac and skeletal muscle. As treatment options for these disease manifestations are very limited, there is a need for novel therapeutic strategies. The present study used a pulmonary arterial hypertension model in female mice to investigate effects of a nutritional combination (containing extra protein, leucine, fish oil and oligosaccharides) presumably targeting pathways involved in cardiac and skeletal muscle remodeling. Methods: Pulmonary arterial hypertension was induced in female mice (C57/BL6) by weekly administration of monocrotaline (MCT; s.c. 600 mg/kg) during 8 weeks, using saline injection as control. During that period, one MCT group (MCT; n=9) and the sham group (Sham; n=9) received a control diet (standard AIN-93M) while a further MCT-treated group received the nutritional intervention (NI, isocaloric) (MCT+NI; n=10). Histological analyses were performed on the RV, tibialis anterior (TA), soleus and extensor digitorum longus (EDL) muscle. Microarray and qRT-PCR analysis for gene expression were performed in RV tissue, and protein analysis by Western blot in tibialis anterior material. Results: Compared to sham mice, MCT mice showed an increase in heart weight by 7%, RV thickness by 13% and fibrosis by 60% (all p<0.05), which were attenuated in MCT+NI mice. Gene Set Enrichment Analysis (GSEA) of array data from the RV confirmed upregulation of fibrotic pathways in the MCT-compared to sham-treated mice (P<0.05), which were downregulated in MCT+NI mice. In addition, skeletal muscle fiber cross-sectional area (CSA) of the tibialis anterior was reduced (P<0.05) by 22% in MCT compared to sham mice, but preserved in the MCT+NI group (1503 vs. 1178 vs 1495 µm2, respectively), with protein expression of the key E3 ligase MuRF1 also reduced by 30% compared to MCT mice alone (p<0.05). In the EDL, CSA was also reduced (p<0.05) by 28% in MCT compared to sham mice and preserved in the group receiving nutritional intervention (764 vs. 542 Vs.742 µm2). No effect of MCT or nutritional intervention was found in the soleus. Conclusions: A multi-compound supplemented nutrition significantly attenuated changes in both cardiac and skeletal muscle in a mouse model of PAH, providing directions for future therapeutic strategies targeting functional decline of both tissues
|Date made available||29 Jul 2019|
Vinke, P. (Creator), Bowen, T. S. (Creator), Boekschoten, M. V. (Creator), Witkamp, R. F. (Creator), Adams, V. (Creator), van Norren, K. (Creator), Hooiveld, G. J. E. J. (Creator) (29 Jul 2019). Anti-inflammatory nutrition with high protein attenuates cardiac and skeletal muscle alterations in a pulmonary arterial hypertension model. Wageningen University.