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Progerin in muscle leads to thermogenic and metabolic defects via impaired calcium homeostasis.


ABSTRACT: 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 Ca2+ 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.

SUBMITTER: Wang WP 

PROVIDER: S-EPMC6996945 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Progerin in muscle leads to thermogenic and metabolic defects via impaired calcium homeostasis.

Wang Wan-Ping WP   Wang Jing-Ya JY   Lin Wen-Hsin WH   Kao Cheng-Heng CH   Hung Ming-Chun MC   Teng Yuan-Chi YC   Tsai Ting-Fen TF   Chi Ya-Hui YH  

Aging cell 20191212 2


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 pro  ...[more]

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