PMID- 35306755
OWN - NLM
STAT- MEDLINE
DCOM- 20220610
LR  - 20220716
IS  - 2190-6009 (Electronic)
IS  - 2190-5991 (Print)
IS  - 2190-5991 (Linking)
VI  - 13
IP  - 3
DP  - 2022 Jun
TI  - Skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone 
      marrow inflammation in male mice.
PG  - 1785-1799
LID - 10.1002/jcsm.12975 [doi]
AB  - BACKGROUND: Mitochondrial oxidative phosphorylation (OxPhos) is a critical 
      regulator of skeletal muscle mass and function. Although muscle atrophy due to 
      mitochondrial dysfunction is closely associated with bone loss, the biological 
      characteristics of the relationship between muscle and bone remain obscure. We 
      showed that muscle atrophy caused by skeletal muscle-specific CR6-interacting 
      factor 1 knockout (MKO) modulates the bone marrow (BM) inflammatory response, 
      leading to low bone mass. METHODS: MKO mice with lower muscle OxPhos were fed a 
      normal chow or high-fat diet and then evaluated for muscle mass and function, and 
      bone mineral density. Immunophenotyping of BM immune cells was also performed. BM 
      transcriptomic analysis was used to identify key factors regulating bone mass in 
      MKO mice. To determine the effects of BM-derived CXCL12 (C-X-C motif chemokine 
      ligand 12) on regulation of bone homeostasis, a variety of BM niche-resident 
      cells were treated with recombinant CXCL12. Vastus lateralis muscle and BM immune 
      cell samples from 14 patients with hip fracture were investigated to examine the 
      association between muscle function and BM inflammation. RESULTS: MKO mice 
      exhibited significant reductions in both muscle mass and expression of OxPhos 
      subunits but increased transcription of mitochondrial stress response-related 
      genes in the extensor digitorum longus (P < 0.01). MKO mice showed a decline in 
      grip strength and a higher drop rate in the wire hanging test (P < 0.01). 
      Micro-computed tomography and von Kossa staining revealed that MKO mice developed 
      a low mass phenotype in cortical and trabecular bone (P < 0.01). Transcriptomic 
      analysis of the BM revealed that mitochondrial stress responses in skeletal 
      muscles induce an inflammatory response and adipogenesis in the BM and that the 
      CXCL12-CXCR4 (C-X-C chemokine receptor 4) axis is important for T-cell homing to 
      the BM. Antagonism of CXCR4 attenuated BM inflammation and increased bone mass in 
      MKO mice. In humans, patients with low body mass index (BMI = 17.2 +/- 0.42 kg/m(2) 
      ) harboured a larger population of proinflammatory and cytotoxic senescent 
      T-cells in the BMI (P < 0.05) and showed reduced expression of OxPhos subunits in 
      the vastus lateralis, compared with controls with a normal BMI 
      (23.7 +/- 0.88 kg/m(2) ) (P < 0.01). CONCLUSIONS: Defects in muscle mitochondrial 
      OxPhos promote BM inflammation in mice, leading to decreased bone mass. Muscle 
      mitochondrial dysfunction is linked to BM inflammatory cytokine secretion via the 
      CXCL12-CXCR4 signalling axis, which is critical for inducing low bone mass.
CI  - (c) 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John 
      Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting 
      Disorders.
FAU - Tian, Jingwen
AU  - Tian J
AD  - Department of Medical Science, Chungnam National University, Daejeon, Korea.
AD  - Laboratory of Endocrinology and Immune System, Chungnam National University 
      School of Medicine, Daejeon, Korea.
FAU - Chung, Hyo Kyun
AU  - Chung HK
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, Korea.
FAU - Moon, Ji Sun
AU  - Moon JS
AD  - Laboratory of Endocrinology and Immune System, Chungnam National University 
      School of Medicine, Daejeon, Korea.
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, Korea.
FAU - Nga, Ha Thi
AU  - Nga HT
AD  - Department of Medical Science, Chungnam National University, Daejeon, Korea.
AD  - Laboratory of Endocrinology and Immune System, Chungnam National University 
      School of Medicine, Daejeon, Korea.
FAU - Lee, Ho Yeop
AU  - Lee HY
AD  - Department of Medical Science, Chungnam National University, Daejeon, Korea.
AD  - Laboratory of Endocrinology and Immune System, Chungnam National University 
      School of Medicine, Daejeon, Korea.
FAU - Kim, Jung Tae
AU  - Kim JT
AD  - Department of Medical Science, Chungnam National University, Daejeon, Korea.
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, Korea.
FAU - Chang, Joon Young
AU  - Chang JY
AD  - Department of Medical Science, Chungnam National University, Daejeon, Korea.
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, Korea.
FAU - Kang, Seul Gi
AU  - Kang SG
AD  - Department of Medical Science, Chungnam National University, Daejeon, Korea.
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, Korea.
FAU - Ryu, Dongryeol
AU  - Ryu D
AD  - Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 
      Suwon, Korea.
AD  - Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
FAU - Che, Xiangguo
AU  - Che X
AD  - Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, 
      BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook 
      National University, Daegu, Korea.
AD  - Department of Internal Medicine, Rheumatology and Immunology, The Affiliated 
      Hospital of Yanbian University, Yanji, China.
FAU - Choi, Je-Yong
AU  - Choi JY
AD  - Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, 
      BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook 
      National University, Daegu, Korea.
FAU - Tsukasaki, Masayuki
AU  - Tsukasaki M
AD  - Department of Immunology, Graduate School of Medicine and Faculty of Medicine, 
      The University of Tokyo, Tokyo, Japan.
FAU - Sasako, Takayoshi
AU  - Sasako T
AD  - Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Lee, Sang-Hee
AU  - Lee SH
AD  - Bio-Electron Microscopy Research Center (104-Dong), Korea Basic Science 
      Institute, Cheongju, Korea.
FAU - Shong, Minho
AU  - Shong M
AD  - Department of Medical Science, Chungnam National University, Daejeon, Korea.
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, Korea.
FAU - Yi, Hyon-Seung
AU  - Yi HS
AUID- ORCID: 0000-0002-3767-1954
AD  - Department of Medical Science, Chungnam National University, Daejeon, Korea.
AD  - Laboratory of Endocrinology and Immune System, Chungnam National University 
      School of Medicine, Daejeon, Korea.
AD  - Research Center for Endocrine and Metabolic Diseases, Chungnam National 
      University School of Medicine, Daejeon, Korea.
LA  - eng
GR  - Korean Endocrine Society of Hyangseol Young Investigator Award/
GR  - Chungnam National University Hospital Research Fund/
GR  - NRF-2017R1E1A1A01075126/National Research Foundation of Korea/
GR  - NRF-2021R1A5A8029876/National Research Foundation of Korea/
GR  - NRF-2019M3E5D1A02068575/National Research Foundation of Korea/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220320
PL  - Germany
TA  - J Cachexia Sarcopenia Muscle
JT  - Journal of cachexia, sarcopenia and muscle
JID - 101552883
SB  - IM
MH  - Animals
MH  - *Bone Marrow/pathology
MH  - Humans
MH  - Inflammation/metabolism
MH  - Male
MH  - Mice
MH  - *Muscle, Skeletal/pathology
MH  - Muscular Atrophy/pathology
MH  - X-Ray Microtomography
PMC - PMC9178379
OTO - NOTNLM
OT  - Bone loss
OT  - Bone marrow
OT  - Inflammation
OT  - Mitochondria
COIS- The authors declare no competing interests.
EDAT- 2022/03/21 06:00
MHDA- 2022/06/11 06:00
PMCR- 2022/06/01
CRDT- 2022/03/20 20:36
PHST- 2022/02/01 00:00 [revised]
PHST- 2021/07/14 00:00 [received]
PHST- 2022/02/15 00:00 [accepted]
PHST- 2022/03/21 06:00 [pubmed]
PHST- 2022/06/11 06:00 [medline]
PHST- 2022/03/20 20:36 [entrez]
PHST- 2022/06/01 00:00 [pmc-release]
AID - JCSM12975 [pii]
AID - 10.1002/jcsm.12975 [doi]
PST - ppublish
SO  - J Cachexia Sarcopenia Muscle. 2022 Jun;13(3):1785-1799. doi: 10.1002/jcsm.12975. 
      Epub 2022 Mar 20.