{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:45:28Z","timestamp":1786977928596,"version":"build-2736575974"},"reference-count":40,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T00:00:00Z","timestamp":1723420800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["MOST 107\u20102314\u2010B\u2010075\u2010012"],"award-info":[{"award-number":["MOST 107\u20102314\u2010B\u2010075\u2010012"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["MOST\u2010108\u20102314\u2010B\u2010075\u2010046"],"award-info":[{"award-number":["MOST\u2010108\u20102314\u2010B\u2010075\u2010046"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["NSTC 110\u20102320\u2010B\u2010A49A\u2010526"],"award-info":[{"award-number":["NSTC 110\u20102320\u2010B\u2010A49A\u2010526"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["NSTC 112\u20102314\u2010B\u2010A49\u2010018"],"award-info":[{"award-number":["NSTC 112\u20102314\u2010B\u2010A49\u2010018"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2024,10]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n \n Sarcopenic obesity is characterized by excess fat mass and diminished muscular mass\/function. DNAJA3, a mitochondrial co\u2010chaperone protein, plays a crucial role in skeletal muscle development. GMI, an immunomodulatory protein, promotes myogenic differentiation through DNAJA3 activation. This study aims to elucidate the physiological effects of muscular\n Dnaja3<\/jats:italic>\n haploinsufficiency on mitochondrial dysfunction and dysregulated lipid metabolism and to assess the efficacy of GMI in rescuing sarcopenic obesity both\n in vitro<\/jats:italic>\n and\n in vivo<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We generated mouse strain with\n Dnaja3<\/jats:italic>\n heterozygosity (\n HSA\u2010Dnaja3<\/jats:italic>\n \n f\/+<\/jats:italic>\n <\/jats:sup>\n ) specifically in skeletal muscle. The body weight, body composition, and locomotor activity of WT and\n HSA\u2010Dnaja3<\/jats:italic>\n \n f\/+<\/jats:italic>\n <\/jats:sup>\n mice were examined. The isolated skeletal muscles and primary myoblasts from the WT and\n HSA\u2010Dnaja3<\/jats:italic>\n \n f\/+<\/jats:italic>\n <\/jats:sup>\n mice, at young or old age, were utilized to study the molecular mechanisms, mitochondrial respiration and ROS level, mitochondrial proteomes, and serological analyses, respectively. To evaluate the therapeutic efficacy of GMI, both short\u2010term and long\u2010term GMI treatment were administrated intraperitoneally to the\n HSA\u2010Dnaja3<\/jats:italic>\n \n f\/+<\/jats:italic>\n <\/jats:sup>\n young (4\u00a0weeks old) or adult (3\u00a0months old) mice for a duration of either 1 or 6\u00a0months, respectively.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Muscular\n Dnaja3<\/jats:italic>\n heterozygosity resulted in impaired locomotor activity (\n P<\/jats:italic>\n \u00a0<\u00a00.05), reduced muscular cross\u2010sectional area (\n P<\/jats:italic>\n \u00a0<\u00a00.0001), and up\u2010regulation of lipogenesis (ACC2) and pro\u2010inflammation (STAT3) in skeletal muscles (\n P<\/jats:italic>\n \u00a0<\u00a00.05). Primary myoblasts from the\n HSA\u2010Dnaja3<\/jats:italic>\n \n f\/+<\/jats:italic>\n <\/jats:sup>\n mice displayed impaired mitochondrial respiration (\n P<\/jats:italic>\n \u00a0<\u00a00.01) and imbalanced mitochondrial ROS levels. A systemic proteomic analysis of the purified mitochondria from the primary myoblasts was conducted to show the abnormalities in mitochondrial function and fatty acid metabolism (\n P<\/jats:italic>\n \u00a0<\u00a00.0001). At age of 13 to 14\u00a0months, the\n HSA\u2010Dnaja3<\/jats:italic>\n \n f\/+<\/jats:italic>\n <\/jats:sup>\n mice displayed increased body fat mass (\n P<\/jats:italic>\n \u00a0<\u00a00.001), reduced fat\u2010free mass (\n P<\/jats:italic>\n \u00a0<\u00a00.01), and impaired glucose and insulin tolerance (\n P<\/jats:italic>\n \u00a0<\u00a00.01). The short\u2010term GMI treatment improved locomotor activity (\n P<\/jats:italic>\n \u00a0<\u00a00.01) and down\u2010regulated the protein levels of STAT3 (\n P<\/jats:italic>\n \u00a0<\u00a00.05), ACC2, and mitochondrial respiratory complex III (UQCRC2) (\n P<\/jats:italic>\n \u00a0<\u00a00.01) via DNAJA3 activation. The long\u2010term GMI treatment ameliorated fat mass accumulation, glucose intolerance, and systemic inflammation (AST) (\n P<\/jats:italic>\n \u00a0<\u00a00.05) in skeletal muscle, while enhancing thermogenesis (UCP1) (\n P<\/jats:italic>\n \u00a0<\u00a00.01) in eWAT. GMI treatment promoted myogenesis, enhanced oxygen consumption, and ameliorated STAT3 (\n P<\/jats:italic>\n \u00a0<\u00a00.01) through DNAJA3 activation (\n P<\/jats:italic>\n \u00a0<\u00a00.05)\n in vitro<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Muscular\n Dnaja3<\/jats:italic>\n haploinsufficiency dysregulates mitochondrial function and lipid metabolism then leads to sarcopenic obesity. GMI emerges as a therapeutic regimen for sarcopenic obesity treatment through DNAJA3 activation.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.13549","type":"journal-article","created":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T06:05:55Z","timestamp":1723442755000},"page":"2013-2029","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Regimen on\n Dnaja3<\/i>\n haploinsufficiency mediated sarcopenic obesity with imbalanced mitochondrial homeostasis and lipid metabolism"],"prefix":"10.1002","volume":"15","author":[{"given":"Yu\u2010Ning","family":"Fann","sequence":"first","affiliation":[{"name":"Institute of Pharmacology, College of Medicine National Yang Ming Chiao Tung University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan\u2010Huai","family":"Teo","sequence":"additional","affiliation":[{"name":"Institute of Oral Biology, College of Dentistry National Yang Ming Chiao 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Chiao Tung University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tung\u2010Fu","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Medicine, College of Medicine National Yang Ming Chiao Tung University Taipei Taiwan"},{"name":"Department of Orthopedics and Traumatology Taipei Veterans General Hospital Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7188-9140","authenticated-orcid":false,"given":"Jeng\u2010Fan","family":"Lo","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, College of Medicine National Yang Ming Chiao Tung University Taipei Taiwan"},{"name":"Institute of Oral Biology, College of Dentistry National Yang Ming Chiao Tung University Taipei Taiwan"},{"name":"Cancer Progression Research Center National Yang Ming Chiao Tung University Taipei Taiwan"},{"name":"Department of Dentistry, College of Dentistry National Yang Ming Chiao Tung 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