Alterations in cardiac function correlate with a disruption in fatty acid metabolism in a mouse model of SMA

Nair, NN, Kline, RA, Boyd, I, Anikumar, M, Thomson, A, Lamont, DJ, Gray, GA, Wishart, TM ORCID: https://orcid.org/0000-0002-1973-6654 and Murray, LM, 2025. Alterations in cardiac function correlate with a disruption in fatty acid metabolism in a mouse model of SMA. Human Molecular Genetics. ISSN 0964-6906

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Abstract

Spinal Muscular Atrophy is an autosomal dominant disease caused by mutations and deletions within the SMN1 gene, with predominantly childhood onset. Although primarily a motor neuron disease, defects in non-neuronal tissues are described in both patients and mouse models. Here, we have undertaken a detailed study of the heart in the Smn2B/− mouse models of SMA, and reveal a thinning of the ventriclar walls as previously described in more severe mouse models of SMA. However most structural changes are resolved by accounting for the smaller body size of the SMA mouse, as was also confirmed in the SMN∆7 model. Echocardiography revealed increased systolic function, which was particularly pronounced in subsets of mice and an increase in global longitudinal strain, collectively indicative of increased cardiac stress in the Smn2B/− mouse model. We have used TMT proteomics to perform a longitudinal study of the proteome of the hearts of Smn2B/− mice and reveal a progressive dysregulation of LXR/RXR signalling which is a regulator of lipid metabolism. We further show consistent perturbations in lipid metabolism in the Smn2B/−, Smn−/−;SMN2;SmnΔ7and SmnΔ7/Δ7;SMN2 mouse models of SMA on the day of birth. This work indicates that although structural changes in the heart can be overstated by failing to account for body size, there are functional defects which could predispose the heart to subsequent failure. We identify a common molecular signature across mouse models pointing to a dysregulation in lipid metabolism, and suggest that manipulation of LXR/RXR signalling offers an opportunity to impact upon these pathways.

Item Type:	Journal article
Publication Title:	Human Molecular Genetics
Creators:	Nair, N.N., Kline, R.A., Boyd, I., Anikumar, M., Thomson, A., Lamont, D.J., Gray, G.A., Wishart, T.M. and Murray, L.M.
Publisher:	Oxford University Press
Date:	15 January 2025
ISSN:	0964-6906
Identifiers:	Number Type 10.1093/hmg/ddaf006 DOI 2371145 Other
Rights:	© the author(s) 2025. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	24 Feb 2025 10:11
Last Modified:	24 Feb 2025 10:11
URI:	https://irep.ntu.ac.uk/id/eprint/53115

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