Skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone marrow inflammation in male mice
Abstract 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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-06-01
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| Series: | Journal of Cachexia, Sarcopenia and Muscle |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jcsm.12975 |
| _version_ | 1797203514781335552 |
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| author | Jingwen Tian Hyo Kyun Chung Ji Sun Moon Ha Thi Nga Ho Yeop Lee Jung Tae Kim Joon Young Chang Seul Gi Kang Dongryeol Ryu Xiangguo Che Je‐Yong Choi Masayuki Tsukasaki Takayoshi Sasako Sang‐Hee Lee Minho Shong Hyon‐Seung Yi |
| author_facet | Jingwen Tian Hyo Kyun Chung Ji Sun Moon Ha Thi Nga Ho Yeop Lee Jung Tae Kim Joon Young Chang Seul Gi Kang Dongryeol Ryu Xiangguo Che Je‐Yong Choi Masayuki Tsukasaki Takayoshi Sasako Sang‐Hee Lee Minho Shong Hyon‐Seung Yi |
| author_sort | Jingwen Tian |
| collection | DOAJ |
| description | Abstract 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/m2) 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/m2) (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. |
| first_indexed | 2024-04-24T08:20:33Z |
| format | Article |
| id | doaj.art-9642f574119e4bc3998ae75d78625e53 |
| institution | Directory Open Access Journal |
| issn | 2190-5991 2190-6009 |
| language | English |
| last_indexed | 2024-04-24T08:20:33Z |
| publishDate | 2022-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj.art-9642f574119e4bc3998ae75d78625e532024-04-17T01:17:52ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092022-06-011331785179910.1002/jcsm.12975Skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone marrow inflammation in male miceJingwen Tian0Hyo Kyun Chung1Ji Sun Moon2Ha Thi Nga3Ho Yeop Lee4Jung Tae Kim5Joon Young Chang6Seul Gi Kang7Dongryeol Ryu8Xiangguo Che9Je‐Yong Choi10Masayuki Tsukasaki11Takayoshi Sasako12Sang‐Hee Lee13Minho Shong14Hyon‐Seung Yi15Department of Medical Science Chungnam National University Daejeon KoreaResearch Center for Endocrine and Metabolic Diseases Chungnam National University School of Medicine Daejeon KoreaLaboratory of Endocrinology and Immune System Chungnam National University School of Medicine Daejeon KoreaDepartment of Medical Science Chungnam National University Daejeon KoreaDepartment of Medical Science Chungnam National University Daejeon KoreaDepartment of Medical Science Chungnam National University Daejeon KoreaDepartment of Medical Science Chungnam National University Daejeon KoreaDepartment of Medical Science Chungnam National University Daejeon KoreaDepartment of Molecular Cell Biology Sungkyunkwan University School of Medicine Suwon KoreaDepartment of Biochemistry and Cell Biology, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, School of Medicine Kyungpook National University Daegu KoreaDepartment of Biochemistry and Cell Biology, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, School of Medicine Kyungpook National University Daegu KoreaDepartment of Immunology, Graduate School of Medicine and Faculty of Medicine The University of Tokyo Tokyo JapanDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine The University of Tokyo Tokyo JapanBio‐Electron Microscopy Research Center (104‐Dong) Korea Basic Science Institute Cheongju KoreaDepartment of Medical Science Chungnam National University Daejeon KoreaDepartment of Medical Science Chungnam National University Daejeon KoreaAbstract 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/m2) 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/m2) (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.https://doi.org/10.1002/jcsm.12975MitochondriaInflammationBone marrowBone loss |
| spellingShingle | Jingwen Tian Hyo Kyun Chung Ji Sun Moon Ha Thi Nga Ho Yeop Lee Jung Tae Kim Joon Young Chang Seul Gi Kang Dongryeol Ryu Xiangguo Che Je‐Yong Choi Masayuki Tsukasaki Takayoshi Sasako Sang‐Hee Lee Minho Shong Hyon‐Seung Yi Skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone marrow inflammation in male mice Journal of Cachexia, Sarcopenia and Muscle Mitochondria Inflammation Bone marrow Bone loss |
| title | Skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone marrow inflammation in male mice |
| title_full | Skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone marrow inflammation in male mice |
| title_fullStr | Skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone marrow inflammation in male mice |
| title_full_unstemmed | Skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone marrow inflammation in male mice |
| title_short | Skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone marrow inflammation in male mice |
| title_sort | skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone marrow inflammation in male mice |
| topic | Mitochondria Inflammation Bone marrow Bone loss |
| url | https://doi.org/10.1002/jcsm.12975 |
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