# Mesenchymal stem cell-specific Sirt1 overexpression prevents sarcopenia induced by 1,25-dihydroxyvitamin D deficiency

## TL;DR

This study shows that boosting Sirt1 in mesenchymal stem cells can prevent muscle loss caused by vitamin D deficiency, offering a new approach to combat aging-related muscle decline.

## Contribution

The study reveals that Sirt1 overexpression in mesenchymal stem cells can counteract sarcopenia caused by vitamin D deficiency through specific molecular mechanisms.

## Key findings

- 1,25(OH)2D3 increases Sirt1 and MyoD1 expression in myoblasts via VDR-mediated transcription.
- Sirt1 overexpression in MSCs improves muscle mass and fiber characteristics in vitamin D-deficient mice.
- Sirt1 reduces muscle cell senescence and SASP by modulating p53 and p65 acetylation and localization.

## Abstract

Sarcopenia, characterized by an age-related decline in skeletal muscle mass and function, is closely linked to vitamin D deficiency. This study examines the role of Sirtuin 1 (Sirt1) and its regulation by vitamin D in preventing sarcopenia. Utilizing wild-type, 1α-hydroxylase knockout (1α(OH)ase−/−), and Sirt1 transgenic (Sirt1Tg) 1α(OH)ase−/− mice, we investigated muscle Sirt1 levels, muscle mass, fiber type, and senescence markers. Our results demonstrated that 1,25-Dihydroxyvitamin D (1,25(OH)2D3) upregulated Sirt1 and myogenic factor MyoD1 expression in C2C12 myoblasts via VDR-mediated transcription. Sirt1 overexpression in mesenchymal stem cells (MSCs) significantly mitigated muscle mass reduction, improved fiber cross-sectional area, and increased type II fiber numbers in 1α(OH)ase−/− mice. Mechanistically, 1,25(OH)2D3 promoted muscle cell health by enhancing Sirt1 expression, which in turn reduced muscle cell senescence and the senescence-associated secretory phenotype (SASP) through decreased levels of acetylated nuclear p53 and p65, maintaining their cytoplasmic localization. Additionally, Sirt1 overexpression accelerated muscle regeneration post-injury by increasing embryonic myosin heavy chain expression and cell proliferation. These findings underscore the therapeutic potential of targeting vitamin D and Sirt1 pathways to prevent sarcopenia, suggesting that supplementation with active vitamin D and consequent Sirt1 activation could be effective strategies for managing age-related muscle wasting.