Vitamin D protects against immobilization-induced muscle atrophy via neural crest-derived cells in mice

Satoshi Nakamura,Kana Miyamoto,Takeshi Miyamoto,Morio Matsumoto,Eri Ito,Yuiko Sato,Arihiko Kanaji,Tomoya Soma,Akihito Oya,Yosuke Kaneko,Masaya Nakamura,Tami Kobayashi,Hiroyuki Okada

doi:10.1038/s41598-020-69021-y

Satoshi Nakamura, Kana Miyamoto + Show 11 more

Open Access

https://doi.org/10.1038/s41598-020-69021-y

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Abstract

Vitamin D deficiency is a recognized risk factor for sarcopenia development, but mechanisms underlying this outcome are unclear. Here, we show that low vitamin D status worsens immobilization-induced muscle atrophy in mice. Mice globally lacking vitamin D receptor (VDR) exhibited more severe muscle atrophy following limb immobilization than controls. Moreover, immobilization-induced muscle atrophy was worse in neural crest-specific than in skeletal muscle-specific VDR-deficient mice. Tnfα expression was significantly higher in immobilized muscle of VDR-deficient relative to control mice, and was significantly elevated in neural crest-specific but not muscle-specific VDR-deficient mice. Furthermore, muscle atrophy induced by limb immobilization in low vitamin D mice was significantly inhibited in Tnfα-deficient mice. We conclude that vitamin D antagonizes immobilization-induced muscle atrophy via VDR expressed in neural crest-derived cells.

Highlights

Vitamin D deficiency is a recognized risk factor for sarcopenia development, but mechanisms underlying this outcome are unclear
These results suggest vitamin D deficiency is a risk for sarcopenia, falls and fragility fractures, it remains unclear how vitamin D prevents these risks
Vitamin D plays a pivotal role in calcium homeostasis, and either vitamin D deficiency or vitamin D receptor (VDR) mutation/deficiency promotes development of rickets in humans and m ice[11,12,13]

Summary

Introduction

Vitamin D deficiency is a recognized risk factor for sarcopenia development, but mechanisms underlying this outcome are unclear. Immobilization-induced muscle atrophy was worse in neural crest-specific than in skeletal musclespecific VDR-deficient mice. Muscle atrophy induced by limb immobilization in low vitamin D mice was significantly inhibited in Tnfα-deficient mice. We conclude that vitamin D antagonizes immobilization-induced muscle atrophy via VDR expressed in neural crest-derived cells. Several meta-analyses report that vitamin D activity can prevent falls[6,7,8,9], and most hip fractures reportedly occur due to falls[10] Taken together, these results suggest vitamin D deficiency is a risk for sarcopenia, falls and fragility fractures, it remains unclear how vitamin D prevents these risks. VDR is required for Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano‐machi, Shinjuku‐ku, Tokyo 160‐8582, Japan. Smad2/3 activities promote expression of the ubiquitin ligases Atrogin-1 and MuRF1, leading to muscle protein degradation and muscle a trophy[28]

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