{"title":"针对 Dnaja3 单倍体缺失介导的肌肉疏松性肥胖以及线粒体平衡和脂质代谢失衡的治疗方案。","authors":"Yu-Ning Fann, Wan-Huai Teo, Hsin-Chen Lee, Chen-Chung Liao, Yeou-Guang Tsay, Tung-Fu Huang, Jeng-Fan Lo","doi":"10.1002/jcsm.13549","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Sarcopenic obesity is characterized by excess fat mass and diminished muscular mass/function. DNAJA3, a mitochondrial co-chaperone 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 <i>Dnaja3</i> haploinsufficiency on mitochondrial dysfunction and dysregulated lipid metabolism and to assess the efficacy of GMI in rescuing sarcopenic obesity both <i>in vitro</i> and <i>in vivo</i>.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We generated mouse strain with <i>Dnaja3</i> heterozygosity (<i>HSA-Dnaja3</i><sup><i>f/+</i></sup>) specifically in skeletal muscle. The body weight, body composition, and locomotor activity of WT and <i>HSA-Dnaja3</i><sup><i>f/+</i></sup> mice were examined. The isolated skeletal muscles and primary myoblasts from the WT and <i>HSA-Dnaja3</i><sup><i>f/+</i></sup> 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-term and long-term GMI treatment were administrated intraperitoneally to the <i>HSA-Dnaja3</i><sup><i>f/+</i></sup> young (4 weeks old) or adult (3 months old) mice for a duration of either 1 or 6 months, respectively.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Muscular <i>Dnaja3</i> heterozygosity resulted in impaired locomotor activity (<i>P</i> < 0.05), reduced muscular cross-sectional area (<i>P</i> < 0.0001), and up-regulation of lipogenesis (ACC2) and pro-inflammation (STAT3) in skeletal muscles (<i>P</i> < 0.05). Primary myoblasts from the <i>HSA-Dnaja3</i><sup><i>f/+</i></sup> mice displayed impaired mitochondrial respiration (<i>P</i> < 0.01) 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 (<i>P</i> < 0.0001). At age of 13 to 14 months, the <i>HSA-Dnaja3</i><sup><i>f/+</i></sup> mice displayed increased body fat mass (<i>P</i> < 0.001), reduced fat-free mass (<i>P</i> < 0.01), and impaired glucose and insulin tolerance (<i>P</i> < 0.01). The short-term GMI treatment improved locomotor activity (<i>P</i> < 0.01) and down-regulated the protein levels of STAT3 (<i>P</i> < 0.05), ACC2, and mitochondrial respiratory complex III (UQCRC2) (<i>P</i> < 0.01) via DNAJA3 activation. The long-term GMI treatment ameliorated fat mass accumulation, glucose intolerance, and systemic inflammation (AST) (<i>P</i> < 0.05) in skeletal muscle, while enhancing thermogenesis (UCP1) (<i>P</i> < 0.01) in eWAT. GMI treatment promoted myogenesis, enhanced oxygen consumption, and ameliorated STAT3 (<i>P</i> < 0.01) through DNAJA3 activation (<i>P</i> < 0.05) <i>in vitro</i>.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Muscular <i>Dnaja3</i> 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.</p>\n </section>\n </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 5","pages":"2013-2029"},"PeriodicalIF":9.4000,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446717/pdf/","citationCount":"0","resultStr":"{\"title\":\"Regimen on Dnaja3 haploinsufficiency mediated sarcopenic obesity with imbalanced mitochondrial homeostasis and lipid metabolism\",\"authors\":\"Yu-Ning Fann, Wan-Huai Teo, Hsin-Chen Lee, Chen-Chung Liao, Yeou-Guang Tsay, Tung-Fu Huang, Jeng-Fan Lo\",\"doi\":\"10.1002/jcsm.13549\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Sarcopenic obesity is characterized by excess fat mass and diminished muscular mass/function. DNAJA3, a mitochondrial co-chaperone 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 <i>Dnaja3</i> haploinsufficiency on mitochondrial dysfunction and dysregulated lipid metabolism and to assess the efficacy of GMI in rescuing sarcopenic obesity both <i>in vitro</i> and <i>in vivo</i>.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>We generated mouse strain with <i>Dnaja3</i> heterozygosity (<i>HSA-Dnaja3</i><sup><i>f/+</i></sup>) specifically in skeletal muscle. The body weight, body composition, and locomotor activity of WT and <i>HSA-Dnaja3</i><sup><i>f/+</i></sup> mice were examined. The isolated skeletal muscles and primary myoblasts from the WT and <i>HSA-Dnaja3</i><sup><i>f/+</i></sup> 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-term and long-term GMI treatment were administrated intraperitoneally to the <i>HSA-Dnaja3</i><sup><i>f/+</i></sup> young (4 weeks old) or adult (3 months old) mice for a duration of either 1 or 6 months, respectively.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Muscular <i>Dnaja3</i> heterozygosity resulted in impaired locomotor activity (<i>P</i> < 0.05), reduced muscular cross-sectional area (<i>P</i> < 0.0001), and up-regulation of lipogenesis (ACC2) and pro-inflammation (STAT3) in skeletal muscles (<i>P</i> < 0.05). Primary myoblasts from the <i>HSA-Dnaja3</i><sup><i>f/+</i></sup> mice displayed impaired mitochondrial respiration (<i>P</i> < 0.01) 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 (<i>P</i> < 0.0001). At age of 13 to 14 months, the <i>HSA-Dnaja3</i><sup><i>f/+</i></sup> mice displayed increased body fat mass (<i>P</i> < 0.001), reduced fat-free mass (<i>P</i> < 0.01), and impaired glucose and insulin tolerance (<i>P</i> < 0.01). The short-term GMI treatment improved locomotor activity (<i>P</i> < 0.01) and down-regulated the protein levels of STAT3 (<i>P</i> < 0.05), ACC2, and mitochondrial respiratory complex III (UQCRC2) (<i>P</i> < 0.01) via DNAJA3 activation. The long-term GMI treatment ameliorated fat mass accumulation, glucose intolerance, and systemic inflammation (AST) (<i>P</i> < 0.05) in skeletal muscle, while enhancing thermogenesis (UCP1) (<i>P</i> < 0.01) in eWAT. GMI treatment promoted myogenesis, enhanced oxygen consumption, and ameliorated STAT3 (<i>P</i> < 0.01) through DNAJA3 activation (<i>P</i> < 0.05) <i>in vitro</i>.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>Muscular <i>Dnaja3</i> 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.</p>\\n </section>\\n </div>\",\"PeriodicalId\":48911,\"journal\":{\"name\":\"Journal of Cachexia Sarcopenia and Muscle\",\"volume\":\"15 5\",\"pages\":\"2013-2029\"},\"PeriodicalIF\":9.4000,\"publicationDate\":\"2024-08-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446717/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Cachexia Sarcopenia and Muscle\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/jcsm.13549\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GERIATRICS & GERONTOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Cachexia Sarcopenia and Muscle","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jcsm.13549","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GERIATRICS & GERONTOLOGY","Score":null,"Total":0}
Regimen on Dnaja3 haploinsufficiency mediated sarcopenic obesity with imbalanced mitochondrial homeostasis and lipid metabolism
Background
Sarcopenic obesity is characterized by excess fat mass and diminished muscular mass/function. DNAJA3, a mitochondrial co-chaperone 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 Dnaja3 haploinsufficiency on mitochondrial dysfunction and dysregulated lipid metabolism and to assess the efficacy of GMI in rescuing sarcopenic obesity both in vitro and in vivo.
Methods
We generated mouse strain with Dnaja3 heterozygosity (HSA-Dnaja3f/+) specifically in skeletal muscle. The body weight, body composition, and locomotor activity of WT and HSA-Dnaja3f/+ mice were examined. The isolated skeletal muscles and primary myoblasts from the WT and HSA-Dnaja3f/+ 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-term and long-term GMI treatment were administrated intraperitoneally to the HSA-Dnaja3f/+ young (4 weeks old) or adult (3 months old) mice for a duration of either 1 or 6 months, respectively.
Results
Muscular Dnaja3 heterozygosity resulted in impaired locomotor activity (P < 0.05), reduced muscular cross-sectional area (P < 0.0001), and up-regulation of lipogenesis (ACC2) and pro-inflammation (STAT3) in skeletal muscles (P < 0.05). Primary myoblasts from the HSA-Dnaja3f/+ mice displayed impaired mitochondrial respiration (P < 0.01) 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 (P < 0.0001). At age of 13 to 14 months, the HSA-Dnaja3f/+ mice displayed increased body fat mass (P < 0.001), reduced fat-free mass (P < 0.01), and impaired glucose and insulin tolerance (P < 0.01). The short-term GMI treatment improved locomotor activity (P < 0.01) and down-regulated the protein levels of STAT3 (P < 0.05), ACC2, and mitochondrial respiratory complex III (UQCRC2) (P < 0.01) via DNAJA3 activation. The long-term GMI treatment ameliorated fat mass accumulation, glucose intolerance, and systemic inflammation (AST) (P < 0.05) in skeletal muscle, while enhancing thermogenesis (UCP1) (P < 0.01) in eWAT. GMI treatment promoted myogenesis, enhanced oxygen consumption, and ameliorated STAT3 (P < 0.01) through DNAJA3 activation (P < 0.05) in vitro.
Conclusions
Muscular Dnaja3 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.
期刊介绍:
The Journal of Cachexia, Sarcopenia and Muscle is a peer-reviewed international journal dedicated to publishing materials related to cachexia and sarcopenia, as well as body composition and its physiological and pathophysiological changes across the lifespan and in response to various illnesses from all fields of life sciences. The journal aims to provide a reliable resource for professionals interested in related research or involved in the clinical care of affected patients, such as those suffering from AIDS, cancer, chronic heart failure, chronic lung disease, liver cirrhosis, chronic kidney failure, rheumatoid arthritis, or sepsis.