Translational Research Institute, AdventHealth, Orlando, Florida, United States.
Icahn School of Medicine at Mount Sinai, New York City, New York, United States.
Am J Physiol Endocrinol Metab. 2023 Oct 1;325(4):E291-E302. doi: 10.1152/ajpendo.00143.2023. Epub 2023 Aug 16.
Insulin resistance and blunted mitochondrial capacity in skeletal muscle are often synonymous, however, this association remains controversial. The aim of this study was to perform an in-depth multifactorial comparison of skeletal muscle mitochondrial capacity between individuals who were lean and active (Active, = 9), individuals with obesity (Obese, = 9), and individuals with obesity, insulin resistance, and type 2 diabetes (T2D, = 22). Mitochondrial capacity was assessed by ex vivo mitochondrial respiration with fatty-acid and glycolytic-supported protocols adjusted for mitochondrial content (mtDNA and citrate synthase activity). Supercomplex assembly was measured by Blue Native (BN)-PAGE and immunoblot. Tricarboxylic (TCA) cycle intermediates were assessed with targeted metabolomics. Exploratory transcriptomics and DNA methylation analyses were performed to uncover molecular differences affecting mitochondrial function among the three groups. We reveal no discernable differences in skeletal muscle mitochondrial content, mitochondrial capacity, supercomplex assembly, TCA cycle intermediates, and mitochondrial molecular profiles between obese individuals with and without T2D that had comparable levels of confounding factors (body mass index, age, and aerobic capacity). We highlight that lean, active individuals have greater mitochondrial content, mitochondrial capacity, supercomplex assembly, and TCA cycle intermediates. These phenotypical changes are reflected at the level of DNA methylation and gene transcription. The collective observation of comparable muscle mitochondrial capacity in individuals with obesity and T2D (vs. individuals without T2D) underscores a dissociation from skeletal muscle insulin resistance. Clinical trial number: NCT01911104. Whether impaired mitochondrial capacity contributes to skeletal muscle insulin resistance is debated. Our multifactorial analysis shows no differences in skeletal muscle mitochondrial content, mitochondrial capacity, and mitochondrial molecular profiles between obese individuals with and without T2D that had comparable levels of confounding factors (BMI, age, aerobic capacity). We highlight that lean, active individuals have enhanced skeletal muscle mitochondrial capacity that is also reflected at the level of DNA methylation and gene transcription.
胰岛素抵抗和骨骼肌线粒体功能受损通常是同义词，但这种关联仍存在争议。本研究的目的是对瘦且活跃的个体（活跃组，n=9）、肥胖个体（肥胖组，n=9）和肥胖、胰岛素抵抗及 2 型糖尿病个体（T2D 组，n=22）的骨骼肌线粒体功能进行深入的多因素比较。通过调整线粒体含量（mtDNA 和柠檬酸合酶活性）的脂肪酸和糖酵解支持的体外线粒体呼吸来评估线粒体功能。通过 Blue Native (BN)-PAGE 和免疫印迹评估超级复合物组装。通过靶向代谢组学评估三羧酸（TCA）循环中间产物。进行探索性转录组学和 DNA 甲基化分析，以揭示影响三组线粒体功能的分子差异。我们发现肥胖个体中 T2D 患者和无 T2D 患者之间在骨骼肌线粒体含量、线粒体功能、超级复合物组装、TCA 循环中间产物和线粒体分子特征方面没有明显差异，且这些患者具有相似水平的混杂因素（体重指数、年龄和有氧能力）。我们强调瘦、活跃的个体具有更高的线粒体含量、线粒体功能、超级复合物组装和 TCA 循环中间产物。这些表型变化反映在 DNA 甲基化和基因转录水平上。肥胖个体中 T2D 患者和无 T2D 患者之间骨骼肌线粒体功能相似的观察结果强调了与骨骼肌胰岛素抵抗的分离。临床试验编号：NCT01911104。线粒体功能受损是否导致骨骼肌胰岛素抵抗仍存在争议。我们的多因素分析表明，肥胖个体中 T2D 患者和无 T2D 患者之间在骨骼肌线粒体含量、线粒体功能和线粒体分子特征方面没有差异，且这些患者具有相似水平的混杂因素（BMI、年龄、有氧能力）。我们强调瘦、活跃的个体具有增强的骨骼肌线粒体功能，这种功能也反映在 DNA 甲基化和基因转录水平上。
