期刊
AGING CELL
卷 19, 期 2, 页码 -出版社
WILEY
DOI: 10.1111/acel.13090
关键词
aging; calcium homeostasis; lamin A; muscular dystrophy; progeria
资金
- Ministry of Science and Technology [104-2633-B-400-001, 105-2320-B-400-020, 105-2633-B-400-001, 107-2319-B-001-002]
- National Taiwan University
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.
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