1,25-Dihydroxyvitamin D deficiency induces sarcopenia by inducing skeletal muscle cell senescence

Shuxiang Yu; Biqi Ren; Haiyun Chen; David Goltzman; Jianshe Yan; Dengshun Miao

1,25-Dihydroxyvitamin D deficiency induces sarcopenia by inducing skeletal muscle cell senescence

Am J Transl Res. 2021 Nov 15;13(11):12638-12649. eCollection 2021.

Authors

Shuxiang Yu^{1

2

3}, Biqi Ren², Haiyun Chen⁴, David Goltzman⁵, Jianshe Yan¹, Dengshun Miao^{2

4}

Affiliations

¹ School of Medicine, Shanghai University Shanghai, China.
² Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Key Laboratory for Aging & Disease, Nanjing Medical University Nanjing, China.
³ School of Environmental and Chemical Engineering, Shanghai University Shanghai, China.
⁴ The Research Center for Aging, Friendship Affiliated Plastic Surgery Hospital of Nanjing Medical University Nanjing, China.
⁵ Calcium Research Laboratory, McGill University Health Centre and Department of Medicine, McGill University Montreal, Canada.

PMID: 34956479
PMCID: PMC8661220

Abstract

To determine if 1,25(OH)₂D deficiency can induce age-related sarcopenia, the skeletal muscular phenotype of male wild-type (WT) and Cyp27b1 knockout (KO) mice were compared at 3 and 6 months of age. We found that muscle mass, grip strength and muscle fiber size were significantly decreased in aging Cyp27b1 KO male mice. The expression levels of genes related to mitochondrial metabolic activity, and antioxidant enzymes including SOD1, catalase, Nqo1 and Gcs were significantly down-regulated in skeletal muscle tissue of Cyp27b1 KO male mice; in contrast, the percentage of p16⁺ and p21⁺ myofibers, and the expression of p16, p19, p21, p53, TNFα, IL6 and MMP3 at mRNA and/or protein levels were significantly increased. We then injected tibialis anterior muscle of WT and Cyp27b1^+/- male mice with BaCl₂, and analyzed the regenerative ability of skeletal muscle cells 7 days later. The results revealed that the numbers of newly formed regenerating central nucleated fibers (CNF), the percentage of BrdU⁺ cells and the expression of MyoD, MyHC and Myf5 at mRNA levels were significantly down-regulated in the injured skeletal muscle tissue of Cyp27b1^+/- mice. In summary, our studies indicate that 1,25(OH)₂D deficiency can result in the development of age-related sarcopenia by inducing oxidative stress, skeletal muscular cell senescence and SASP, and by inhibiting skeletal muscle regeneration. Cyp27b1 KO mice can therefore be used as an animal model of age-related sarcopenia in order to investigate the pathogenesis of age-related sarcopenia and potentially to test intervention measures for treatment of sarcopenia.

Keywords: Vitamin D deficiency; muscular cell senescence and regeneration; oxidative stress; sarcopenia.