家族性部分脂肪营养不良(FPL),邓尼甘品种的特征是骨骼肌肥大和胰岛素抵抗,除了四肢脂肪损失。肌肉肥大的原因及其功能后果尚不清楚。
比较肌肉力量和耐力,除了FPL受试者和匹配对照组之间的肌肉蛋白合成率(每组n=6)。此外,我们研究了骨骼肌线粒体功能和基因表达模式,以帮助理解观察到的差异的机制。
通过双能X射线吸收法测量身体成分,通过最小建模的胰岛素敏感性,评估峰值肌肉力量和疲劳,骨骼肌活检和肌肉蛋白质合成率的计算,线粒体呼吸测定,骨骼肌转录组,蛋白质组,和基因集富集分析。
尽管增加了肌肉组织,FPL受试者没有表现出增加的肌肉力量,但在胸部按压运动中有较早的疲劳。在脂肪酸底物的存在下,线粒体状态3呼吸减少,同时增加肌肉乳酸和减少长链酰基肉碱。基于基因转录组,参与线粒体生物发生和功能的许多关键代谢途径显著下调。此外,基因表达的总体模式表明FPL受试者衰老加速.观察到较低的肌肉蛋白质合成和与肌肉蛋白质分解代谢有关的基因转录物的下调。
FPL中增加的肌肉强度不是由于增加的肌肉蛋白质合成,并且可能是由于减少的肌肉蛋白质降解。线粒体功能受损和基因表达改变可能解释了FPL受试者的代谢异常和骨骼肌功能障碍。
Familial partial lipodystrophy (FPL), Dunnigan variety is characterized by skeletal muscle hypertrophy and insulin resistance besides fat loss from the extremities. The cause for the muscle hypertrophy and its functional consequences is not known.
To compare muscle strength and endurance, besides muscle protein synthesis rate between subjects with FPL and matched controls (n = 6 in each group). In addition, we studied skeletal muscle mitochondrial function and gene expression pattern to help understand the mechanisms for the observed differences.
Body composition by dual-energy X-ray absorptiometry, insulin sensitivity by minimal modelling, assessment of peak muscle strength and fatigue, skeletal muscle biopsy and calculation of muscle protein synthesis rate, mitochondrial respirometry, skeletal muscle transcriptome, proteome, and gene set enrichment analysis.
Despite increased muscularity, FPL subjects did not demonstrate increased muscle strength but had earlier fatigue on chest press exercise. Decreased mitochondrial state 3 respiration in the presence of fatty acid substrate was noted, concurrent to elevated muscle lactate and decreased long-chain acylcarnitine. Based on gene transcriptome, there was significant downregulation of many critical metabolic pathways involved in mitochondrial biogenesis and function. Moreover, the overall pattern of gene expression was indicative of accelerated aging in FPL subjects. A lower muscle protein synthesis and downregulation of gene transcripts involved in muscle protein catabolism was observed.
Increased muscularity in FPL is not due to increased muscle protein synthesis and is likely due to reduced muscle protein degradation. Impaired mitochondrial function and altered gene expression likely explain the metabolic abnormalities and skeletal muscle dysfunction in FPL subjects.