# Signaling pathway alterations in hearts of a porcine model harboring a β-myosin heavy chain (MYH7-R403Q) gene variant

## TL;DR

This study examines how a genetic variant in pigs affects heart signaling pathways, revealing changes in left ventricle and endocardium but not in coronary arteries.

## Contribution

The study identifies specific signaling pathway alterations in a pig model of hypertrophic cardiomyopathy without intervention effects.

## Key findings

- LV and EN samples showed minor phosphorylation changes and significant unmodified protein changes compared to WT.
- Altered pathways included mechano-signaling and inflammation in LV and EN, with metabolic dysfunction more prominent in EN.
- No significant changes were observed in phospho-peptide or unmodified protein abundances in coronary arteries.

## Abstract

The disease-causing myosin variant (MYH7-403Q) is linked to hypertrophic cardiomyopathy (HCM). We carried out a research study of signaling pathways in heart samples from control wild-type (WT) GE Yucatán mini-pigs and their littermates harboring the gene variant, MYH7-R403Q. Our approach permits the determination of adverse signaling pathways involved in different regions of a translationally relevant heart without the effects of intervention. We examined the left ventricular free wall (LV), endocardium (EN), and coronary arteries (CA) from 5 transgenic and 5 wild-type mini-pig littermates to determine alterations in global phosphorylation and protein abundance. Digested peptides from 6 to 7 months old mixed-sex mini-pigs were isobarically labeled; 95 % were phospho-enriched, and 5 % were used as the unmodified (total) fraction. The phospho-enriched and unmodified fractions were injected into an Orbitrap Fusion Lumos and analyzed using PEAKS Studio and Ingenuity Pathway Analysis. Surprisingly, we found no significant changes in the phospho-peptide and unmodified protein abundances in CA. Compared to WT, both LV and EN samples displayed minor changes in phosphorylation and significant changes in unmodified proteins. Bioinformatic analysis revealed that pathways associated with mechano-signaling between cardiomyocytes and the extracellular matrix and inflammation were altered in LV and EN samples. In addition, EN samples had larger differences in pathways related to metabolic dysfunction compared to LV. Our findings provide a translational understanding of signaling pathways altered in the MYH7-R403Q gene variant.

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