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。

IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Journal of Cachexia Sarcopenia and Muscle Pub Date : 2024-08-12 DOI:10.1002/jcsm.13549
Yu-Ning Fann, Wan-Huai Teo, Hsin-Chen Lee, Chen-Chung Liao, Yeou-Guang Tsay, Tung-Fu Huang, Jeng-Fan Lo
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引用次数: 0

摘要

背景:肌肉疏松性肥胖症的特征是脂肪量过多和肌肉质量/功能下降。DNAJA3是一种线粒体辅助伴侣蛋白,在骨骼肌发育过程中起着至关重要的作用。GMI是一种免疫调节蛋白,可通过激活DNAJA3促进肌肉分化。本研究旨在阐明肌肉 Dnaja3 单倍体缺失对线粒体功能障碍和脂质代谢失调的生理影响,并评估 GMI 在体外和体内拯救肌肉疏松性肥胖的功效:方法:我们产生了骨骼肌特异性 Dnaja3 杂合子小鼠品系(HSA-Dnaja3f/+)。我们检测了 WT 和 HSA-Dnaja3f/+ 小鼠的体重、身体成分和运动活性。研究人员利用 WT 小鼠和 HSA-Dnaja3f/+ 小鼠幼年或老年时分离的骨骼肌和原代肌母细胞,分别对其分子机制、线粒体呼吸和 ROS 水平、线粒体蛋白质组和血清学分析进行了研究。为了评估 GMI 的疗效,分别给 HSA-Dnaja3f/+ 幼鼠(4 周大)或成年鼠(3 个月大)腹腔注射短期和长期 GMI,疗程分别为 1 个月或 6 个月:结果:肌肉 Dnaja3 杂合子导致小鼠运动能力受损(P f/+ 小鼠线粒体呼吸能力受损(P f/+ 小鼠体脂量增加(P 结论:肌肉 Dnaja3 杂合子导致小鼠运动能力受损(P f/+ 小鼠线粒体呼吸能力受损(P f/+ 小鼠体脂量增加)):肌肉 Dnaja3 单倍体缺失会导致线粒体功能和脂质代谢失调,进而导致肌肉疏松性肥胖。通过激活 DNAJA3,GMI 成为治疗肌肉疏松性肥胖症的一种疗法。
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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.

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来源期刊
Journal of Cachexia Sarcopenia and Muscle
Journal of Cachexia Sarcopenia and Muscle MEDICINE, GENERAL & INTERNAL-
CiteScore
13.30
自引率
12.40%
发文量
234
审稿时长
16 weeks
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.
期刊最新文献
Issue Information Neuromuscular impairment at different stages of human sarcopenia The impact of mobility limitations on geriatric rehabilitation outcomes: Positive effects of resistance exercise training (RESORT) Artificial neural network inference analysis identified novel genes and gene interactions associated with skeletal muscle aging Hydrogen sulfide inhibits skeletal muscle ageing by up-regulating autophagy through promoting deubiquitination of adenosine 5’-monophosphate (AMP)-activated protein kinase α1 via ubiquitin specific peptidase 5
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