Mesenchymal  Bmp3b  expression maintains skeletal muscle integrity and decreases in age-related sarcopenia

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Abstract

Age-related sarcopenia constitutes an important health problem associated with adverse outcomes. Sarcopenia is closely associated with fat infiltration in muscle, which is attributable to interstitial mesenchymal progenitors. Mesenchymal progenitors are nonmyogenic in nature but are required for homeostatic muscle maintenance. However, the underlying mechanism of mesenchymal progenitor–dependent muscle maintenance is not clear, nor is the precise role of mesenchymal progenitors in sarcopenia. Here, we show that mice genetically engineered to specifically deplete mesenchymal progenitors exhibited phenotypes markedly similar to sarcopenia, including muscle weakness, myofiber atrophy, alterations of fiber types, and denervation at neuromuscular junctions. Through searching for genes responsible for mesenchymal progenitor–dependent muscle maintenance, we found that Bmp3b is specifically expressed in mesenchymal progenitors, whereas its expression level is significantly decreased during aging or adipogenic differentiation. The functional importance of BMP3B in maintaining myofiber mass as well as muscle-nerve interaction was demonstrated using knockout mice and cultured cells treated with BMP3B. Furthermore, the administration of recombinant BMP3B in aged mice reversed their sarcopenic phenotypes. These results reveal previously unrecognized mechanisms by which the mesenchymal progenitors ensure muscle integrity and suggest that age-related changes in mesenchymal progenitors have a considerable impact on the development of sarcopenia.

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Most cited references 11

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Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus

Shankar Srinivas, Tomoko Watanabe, Chyuan-Sheng Lin … (2001)

Background Several Cre reporter strains of mice have been described, in which a lacZ gene is turned on in cells expressing Cre recombinase, as well as their daughter cells, following Cre-mediated excision of a loxP-flanked transcriptional "stop" sequence. These mice are useful for cell lineage tracing experiments as well as for monitoring the expression of Cre transgenes. The green fluorescent protein (GFP) and variants such as EYFP and ECFP offer an advantage over lacZ as a reporter, in that they can be easily visualized without recourse to the vital substrates required to visualize β-gal in living tissue. Results In view of the general utility of targeting the ubiquitously expressed ROSA26 locus, we constructed a generic ROSA26 targeting vector. We then generated two reporter lines of mice by inserting EYFP or ECFP cDNAs into the ROSA26 locus, preceded by a loxP-flanked stop sequence. These strains were tested by crossing them with transgenic strains expressing Cre in a ubiquitous (β-actin-Cre) or a cell-specific (Isl1-Cre and En1-Cre) pattern. The resulting EYFP or ECFP expression patterns indicated that the reporter strains function as faithful monitors of Cre activity. Conclusions In contrast to existing lacZ reporter lines, where lacZ expression cannot easily be detected in living tissue, the EYFP and ECFP reporter strains are useful for monitoring the expression of Cre and tracing the lineage of these cells and their descendants in cultured embryos or organs. The non-overlapping emission spectra of EYFP and ECFP make them ideal for double labeling studies in living tissues.

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Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle.

Ryo Ogawa, M. Segawa, Akiyoshi Uezumi … (2011)

Accumulation of adipocytes and collagen type-I-producing cells (fibrosis) is observed in muscular dystrophies. The origin of these cells had been largely unknown, but recently we identified mesenchymal progenitors positive for platelet-derived growth factor receptor alpha (PDGFRα) as the origin of adipocytes in skeletal muscle. However, the origin of muscle fibrosis remains largely unknown. In this study, clonal analyses show that PDGFRα(+) cells also differentiate into collagen type-I-producing cells. In fact, PDGFRα(+) cells accumulated in fibrotic areas of the diaphragm in the mdx mouse, a model of Duchenne muscular dystrophy. Furthermore, mRNA of fibrosis markers was expressed exclusively in the PDGFRα(+) cell fraction in the mdx diaphragm. Importantly, TGF-β isoforms, known as potent profibrotic cytokines, induced expression of markers of fibrosis in PDGFRα(+) cells but not in myogenic cells. Transplantation studies revealed that fibrogenic PDGFRα(+) cells mainly derived from pre-existing PDGFRα(+) cells and that the contribution of PDGFRα(-) cells and circulating cells was limited. These results indicate that mesenchymal progenitors are the main origin of not only fat accumulation but also fibrosis in skeletal muscle.

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Muscle stem cells contribute to myofibers in sedentary adult mice

Alexandra C. Keefe, Jennifer Lawson, Steven Flygare … (2015)

Skeletal muscle is essential for mobility, stability, and whole body metabolism, and muscle loss, for instance during sarcopenia, has profound consequences. Satellite cells (muscle stem cells) have been hypothesized, but not yet demonstrated, to contribute to muscle homeostasis and a decline in their contribution to myofiber homeostasis to play a part in sarcopenia. To test their role in muscle maintenance, we genetically labeled and ablated satellite cells in adult sedentary mice. We demonstrate via genetic lineage experiments that even in the absence of injury, satellite cells contribute to myofibers in all adult muscles, although the extent and timing differs. However, genetic ablation experiments showed that satellite cells are not globally required to maintain myofiber cross-sectional area of uninjured adult muscle.

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Author and article information

Contributors

Akiyoshi Uezumi:

ORCID: http://orcid.org/0000-0003-4294-0116

Madoka Ikemoto-Uezumi

Heying Zhou

Tamaki Kurosawa

Yuki Yoshimoto

Masashi Nakatani

Keisuke Hitachi:

ORCID: http://orcid.org/0000-0002-7300-5238

Hisateru Yamaguchi:

ORCID: http://orcid.org/0000-0002-4507-9598

Shuji Wakatsuki

Toshiyuki Araki:

ORCID: http://orcid.org/0000-0003-3625-2042

Mitsuhiro Morita:

ORCID: http://orcid.org/0000-0001-6887-3404

Harumoto Yamada

Masashi Toyoda:

ORCID: http://orcid.org/0000-0002-9432-6401

Nobuo Kanazawa

Tatsu Nakazawa

Jun Hino:

ORCID: http://orcid.org/0000-0003-4740-8858

So-ichiro Fukada:

ORCID: http://orcid.org/0000-0003-4051-5108

Kunihiro Tsuchida:

ORCID: http://orcid.org/0000-0002-3983-5756

Journal

Journal ID (nlm-ta): J Clin Invest

Journal ID (iso-abbrev): J Clin Invest

Journal ID (publisher-id): J Clin Invest

Title: The Journal of Clinical Investigation

Publisher: American Society for Clinical Investigation

ISSN (Print): 0021-9738

ISSN (Electronic): 1558-8238

Publication date Created: 4 January 2021

Publication date PMC-release: 4 April 2021

Volume: 131

Issue: 1

Electronic Location Identifier: e139617

Affiliations

[1 ]Muscle Aging and Regenerative Medicine, Tokyo Metropolitan Institute of Gerontology (TMIG), Tokyo, Japan.

[2 ]Faculty of Rehabilitation and Care, Seijoh University, Tokai, Japan.

[3 ]Division for Therapies against Intractable Diseases, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Japan.

[4 ]Department of Medical Technology, School of Nursing and Medical Care, Yokkaichi Nursing and Medical Care University, Yokkaichi, Japan.

[5 ]Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

[6 ]Department of Orthopaedic Surgery, Fujita Health University, Toyoake, Japan.

[7 ]Vascular Medicine, TMIG, Tokyo, Japan.

[8 ]Department of Surgery, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology (TMGHIG), Tokyo, Japan.

[9 ]Seibo Hospital, Tokyo, Japan.

[10 ]Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.

[11 ]Project for Muscle Stem Cell Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.

Author notes

Address correspondence to: Akiyoshi Uezumi, Muscle Aging and Regenerative Medicine, Tokyo Metropolitan Institute of Gerontology (TMIG), 35-2 Sakae-cho, Itabashi, Tokyo 173-0015, Japan. Phone: 81.3.3964.3241; Email: uezumi@ 123456tmig.or.jp .