Mutations in lamin A (LMNA) are responsible for a variety of human dystrophic and metabolic diseases. Here, we created a mouse model in which progerin, the lamin A mutant protein that causes Hutchinson-Gilford progeria syndrome (HGPS), can be inducibly overexpressed. Muscle-specific overexpression of progerin was sufficient to induce muscular dystrophy and alter whole-body energy expenditure, leading to premature death. Intriguingly, sarcolipin (Sln), an endoplasmic reticulum (ER)-associated protein involved in heat production, is upregulated in progerin-expressing and Lmna knockout (Lmna ) skeletal muscle. The depletion of Sln accelerated the early death of Lmna mice. An examination at the molecular level revealed that progerin recruits Sln and Calnexin to the nuclear periphery. Furthermore, progerin-expressing myoblasts presented enhanced store-operated Ca entry, as well as increased co-localization of STIM1 and ORAI1. These findings suggest that progerin dysregulates calcium homeostasis through an interaction with a subset of ER-associated proteins, resulting in thermogenic and metabolic abnormalities.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996945PMC
http://dx.doi.org/10.1111/acel.13090DOI Listing

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