PMID- 38533539
OWN - NLM
STAT- Publisher
LR  - 20240327
IS  - 2190-6009 (Electronic)
IS  - 2190-5991 (Linking)
DP  - 2024 Mar 27
TI  - Lack of vitamin D signalling in mesenchymal progenitors causes fatty infiltration 
      in muscle.
LID - 10.1002/jcsm.13448 [doi]
AB  - BACKGROUND: Recent studies have indicated the importance of muscle quality in 
      addition to muscle quantity in sarcopenia pathophysiology. Intramuscular adipose 
      tissue (IMAT), which originates from mesenchymal progenitors (MPs) in adult 
      skeletal muscle, is a key factor affecting muscle quality in older adults, 
      suggesting that controlling IMAT formation is a promising therapeutic strategy 
      for sarcopenia. However, the molecular mechanism underlying IMAT formation in 
      older adults has not been clarified. We recently found that the vitamin D 
      receptor (VDR) is highly expressed in MPs in comparison to myotubes (P = 0.028, 
      N = 3), indicating a potential role of vitamin D signalling in MPs. In this 
      study, we aimed to clarify the role of vitamin D signalling in MP kinetics, with 
      a focus on adipogenesis. METHODS: MPs isolated from mouse skeletal muscles were 
      subjected to adipogenic differentiation conditions with or without vitamin D 
      (1alpha,25(OH)2D3, 100 nM) for 7 days, and adipogenicity was evaluated based on 
      adipogenic marker expression. For in vivo analysis, tamoxifen-inducible 
      MP-specific VDR-deficient (Vdr(MPcKO)) mice were newly developed to investigate 
      whether lack of vitamin D signalling in MPs is involved in IMAT formation. To 
      induce muscle atrophy, Vdr(MPcKO) male mice were subjected to tenotomy of the 
      gastrocnemius muscle, and then muscle weight, myofibre cross-sectional area, 
      adipogenic marker expression, and fatty infiltration into the muscle were 
      evaluated at 3 weeks after operation (N = 3-4). In addition, a vitamin 
      D-deficient diet was provided to wild-type male mice (3 and 20 months of age, 
      N = 5) for 3 months to investigate whether vitamin D deficiency causes IMAT 
      formation. RESULTS: Vitamin D treatment nearly completely inhibited adipogenesis 
      of MPs through Runx1-mediated transcriptional modifications of early adipogenic 
      factors such as PPARgamma (P = 0.0031) and C/EBPalpha (P = 0.0027), whereas VDR-deficient 
      MPs derived from Vdr(MPcKO) mice differentiated into adipocytes even in the 
      presence of vitamin D (P = 0.0044, Oil-Red O(+) area). In consistency with 
      in-vitro findings, Vdr(MPcKO) mice and mice fed a vitamin D-deficient diet 
      exhibited fat deposition in atrophied (P = 0.0311) and aged (P = 0.0216) skeletal 
      muscle, respectively. CONCLUSIONS: Vitamin D signalling is important to prevent 
      fate decision of MPs towards the adipogenic lineage. As vitamin D levels decline 
      with age, our data indicate that decreased vitamin D levels may be one of the 
      causes of IMAT formation in older adults, and vitamin D signalling may be a novel 
      therapeutic target for sarcopenia.
CI  - (c) 2024 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley 
      Periodicals LLC.
FAU - Hosoyama, Tohru
AU  - Hosoyama T
AUID- ORCID: 0000-0002-1825-6923
AD  - Department of Musculoskeletal Disease, Research Institute, National Center for 
      Geriatrics and Gerontology, Obu, Japan.
FAU - Kawai-Takaishi, Minako
AU  - Kawai-Takaishi M
AD  - Department of Musculoskeletal Disease, Research Institute, National Center for 
      Geriatrics and Gerontology, Obu, Japan.
FAU - Iida, Hiroki
AU  - Iida H
AD  - Department of Musculoskeletal Disease, Research Institute, National Center for 
      Geriatrics and Gerontology, Obu, Japan.
AD  - Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 
      Nagoya, Japan.
FAU - Yamamoto, Yoko
AU  - Yamamoto Y
AD  - Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.
FAU - Nakamichi, Yuko
AU  - Nakamichi Y
AD  - Institute for Oral Science, Matsumoto Dental University, Nagano, Japan.
FAU - Watanabe, Tsuyoshi
AU  - Watanabe T
AD  - Center for Frailty and Locomotive Syndrome, National Center for Geriatrics and 
      Gerontology, Obu, Japan.
AD  - Department of Orthopaedic Surgery, National Center for Geriatrics and 
      Gerontology, Obu, Japan.
FAU - Takemura, Marie
AU  - Takemura M
AD  - Center for Frailty and Locomotive Syndrome, National Center for Geriatrics and 
      Gerontology, Obu, Japan.
FAU - Kato, Shigeaki
AU  - Kato S
AD  - Graduate School of Life Science and Engineering, Iryo Sosei University, 
      Fukushima, Japan.
AD  - Research Institute of Innovative Medicine, Tokiwa Foundation, Fukushima, Japan.
FAU - Uezumi, Akiyoshi
AU  - Uezumi A
AD  - Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
FAU - Matsui, Yasumoto
AU  - Matsui Y
AD  - Center for Frailty and Locomotive Syndrome, National Center for Geriatrics and 
      Gerontology, Obu, Japan.
LA  - eng
GR  - 21-44/Japanese Ministry of Health, Labour and Welfare/
GR  - 21K09289/Japan Society for the Promotion of Science/
GR  - Tanita Healthy Weight Community Promotion Research Grant/
GR  - Zenyaku-Kogyo Research Grant/
PT  - Journal Article
DEP - 20240327
PL  - Germany
TA  - J Cachexia Sarcopenia Muscle
JT  - Journal of cachexia, sarcopenia and muscle
JID - 101552883
SB  - IM
OTO - NOTNLM
OT  - Inter/intramuscular adipose tissue
OT  - Mesenchymal progenitor
OT  - Sarcopenia
OT  - VDR
OT  - Vitamin D
EDAT- 2024/03/27 06:43
MHDA- 2024/03/27 06:43
CRDT- 2024/03/27 04:00
PHST- 2024/01/22 00:00 [revised]
PHST- 2023/09/29 00:00 [received]
PHST- 2024/01/31 00:00 [accepted]
PHST- 2024/03/27 06:43 [medline]
PHST- 2024/03/27 06:43 [pubmed]
PHST- 2024/03/27 04:00 [entrez]
AID - 10.1002/jcsm.13448 [doi]
PST - aheadofprint
SO  - J Cachexia Sarcopenia Muscle. 2024 Mar 27. doi: 10.1002/jcsm.13448.