PDZRN3 regulates adipogenesis of mesenchymal progenitors in muscle
Introduction: Intramuscular adipose tissue (IMAT) is frequently formed in certain pathological conditions, such as biological aging, and ectopic fat accumulation leads to muscle weakness and a subsequent decline in physical function. Although mesenchymal progenitors (MPs) are present in postnatal sk...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-03-01
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| Series: | Regenerative Therapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352320425000185 |
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| author | Hiroki Iida Minako Kawai-Takaishi Yoshihiro Miyagawa Yasuhiko Takegami Akiyoshi Uezumi Takeshi Honda Shiro Imagama Tohru Hosoyama |
| author_facet | Hiroki Iida Minako Kawai-Takaishi Yoshihiro Miyagawa Yasuhiko Takegami Akiyoshi Uezumi Takeshi Honda Shiro Imagama Tohru Hosoyama |
| author_sort | Hiroki Iida |
| collection | DOAJ |
| description | Introduction: Intramuscular adipose tissue (IMAT) is frequently formed in certain pathological conditions, such as biological aging, and ectopic fat accumulation leads to muscle weakness and a subsequent decline in physical function. Although mesenchymal progenitors (MPs) are present in postnatal skeletal muscle and are the cells from which IMAT originates, the molecular mechanism by which MPs contribute to IMAT formation has not been completely elucidated. Recently, we found that PDZ domain-containing ring finger 3 (PDZRN3), an E3-ubiquitin ligase, was highly expressed in MPs. In this study, we aimed to clarify the functions of PDZRN3 in MPs and the roles of PDZRN3 in IMAT formation using in vitro and in vivo experiments. Methods: Primary mouse MPs isolated from hindlimb muscles were applied to adipogenic differentiation conditions, and expression fluctuation of PDZRN3 was verified with adipogenic differentiation and Wnt signaling markers. The role of PDZRN3 on MP’s adipogenesis was evaluated in vitro by gene knock-down experiments. To evaluate the contribution of PDZRN3 to IMAT formation in vivo, tamoxifen-inducible MP-specific Pdzrn3 knockout (Pdzrn3MPcKO) mice were developed. Results: PDZRN3 was more expressed in MPs than in muscle stem cells, and its expression profile of PDZRN3 fluctuated with the adipogenic differentiation of MPs. Our results revealed that PDZRN3 suppressed the adipogenesis of MPs in vitro through the activation of Wnt signaling and that a decrease in PDZRN3 accelerated adipogenesis. Indeed, IMAT significantly increased in the denervated muscles of Pdzrn3MPcKO mice. Conclusions: Our findings suggest that PDZRN3 is a key molecule in regulating IMAT formation. Since ectopic fat accumulation is frequently found in the skeletal muscles of older adults and also muscular dystrophy patients, PDZRN3 and its related pathways may represent a novel therapeutic target for these muscle pathologies. |
| format | Article |
| id | doaj-art-9e62e36dc1ad49a1968d3c7c8adef915 |
| institution | Kabale University |
| issn | 2352-3204 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Regenerative Therapy |
| spelling | doaj-art-9e62e36dc1ad49a1968d3c7c8adef9152025-02-02T05:27:40ZengElsevierRegenerative Therapy2352-32042025-03-0128473480PDZRN3 regulates adipogenesis of mesenchymal progenitors in muscleHiroki Iida0Minako Kawai-Takaishi1Yoshihiro Miyagawa2Yasuhiko Takegami3Akiyoshi Uezumi4Takeshi Honda5Shiro Imagama6Tohru Hosoyama7Department of Musculoskeletal Disease, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, JapanDepartment of Musculoskeletal Disease, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, JapanDepartment of Musculoskeletal Disease, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, JapanDepartment of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, JapanDivision of Cell Heterogeneity, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka, JapanDepartment of Pharmacology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan; Department of Chemistry, Kurume University Graduate School of Medicine, Kurume, Fukuoka, JapanDepartment of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, JapanDepartment of Musculoskeletal Disease, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Corresponding author. Department of Musculoskeletal Disease, Research Institute, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu, Aichi, 474-8511, Japan.Introduction: Intramuscular adipose tissue (IMAT) is frequently formed in certain pathological conditions, such as biological aging, and ectopic fat accumulation leads to muscle weakness and a subsequent decline in physical function. Although mesenchymal progenitors (MPs) are present in postnatal skeletal muscle and are the cells from which IMAT originates, the molecular mechanism by which MPs contribute to IMAT formation has not been completely elucidated. Recently, we found that PDZ domain-containing ring finger 3 (PDZRN3), an E3-ubiquitin ligase, was highly expressed in MPs. In this study, we aimed to clarify the functions of PDZRN3 in MPs and the roles of PDZRN3 in IMAT formation using in vitro and in vivo experiments. Methods: Primary mouse MPs isolated from hindlimb muscles were applied to adipogenic differentiation conditions, and expression fluctuation of PDZRN3 was verified with adipogenic differentiation and Wnt signaling markers. The role of PDZRN3 on MP’s adipogenesis was evaluated in vitro by gene knock-down experiments. To evaluate the contribution of PDZRN3 to IMAT formation in vivo, tamoxifen-inducible MP-specific Pdzrn3 knockout (Pdzrn3MPcKO) mice were developed. Results: PDZRN3 was more expressed in MPs than in muscle stem cells, and its expression profile of PDZRN3 fluctuated with the adipogenic differentiation of MPs. Our results revealed that PDZRN3 suppressed the adipogenesis of MPs in vitro through the activation of Wnt signaling and that a decrease in PDZRN3 accelerated adipogenesis. Indeed, IMAT significantly increased in the denervated muscles of Pdzrn3MPcKO mice. Conclusions: Our findings suggest that PDZRN3 is a key molecule in regulating IMAT formation. Since ectopic fat accumulation is frequently found in the skeletal muscles of older adults and also muscular dystrophy patients, PDZRN3 and its related pathways may represent a novel therapeutic target for these muscle pathologies.http://www.sciencedirect.com/science/article/pii/S2352320425000185Intramuscular adipose tissueMesenchymal progenitorPDZRN3Wnt signaling |
| spellingShingle | Hiroki Iida Minako Kawai-Takaishi Yoshihiro Miyagawa Yasuhiko Takegami Akiyoshi Uezumi Takeshi Honda Shiro Imagama Tohru Hosoyama PDZRN3 regulates adipogenesis of mesenchymal progenitors in muscle Regenerative Therapy Intramuscular adipose tissue Mesenchymal progenitor PDZRN3 Wnt signaling |
| title | PDZRN3 regulates adipogenesis of mesenchymal progenitors in muscle |
| title_full | PDZRN3 regulates adipogenesis of mesenchymal progenitors in muscle |
| title_fullStr | PDZRN3 regulates adipogenesis of mesenchymal progenitors in muscle |
| title_full_unstemmed | PDZRN3 regulates adipogenesis of mesenchymal progenitors in muscle |
| title_short | PDZRN3 regulates adipogenesis of mesenchymal progenitors in muscle |
| title_sort | pdzrn3 regulates adipogenesis of mesenchymal progenitors in muscle |
| topic | Intramuscular adipose tissue Mesenchymal progenitor PDZRN3 Wnt signaling |
| url | http://www.sciencedirect.com/science/article/pii/S2352320425000185 |
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