Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.
Department of Molecular and Integrative Physiology and Internal Medicine-Division of Endocrinology and Metabolism, University of Kansas Medical Center, Kansas City, KS, USA.
Function (Oxf). 2021 Sep 2;2(6):zqab045. doi: 10.1093/function/zqab045. eCollection 2021.
Alzheimer's Disease (ad) associates with insulin resistance and low aerobic capacity, suggestive of impaired skeletal muscle mitochondrial function. However, this has not been directly measured in AD. This study ( = 50) compared muscle mitochondrial respiratory function and gene expression profiling in cognitively healthy older adults (CH; = 24) to 26 individuals in the earliest phase of ad-related cognitive decline, mild cognitive impairment (MCI; = 11) or MCI taking the ad medication donepezil (MCI + med; = 15). Mitochondrial respiratory kinetics were measured in permeabilized muscle fibers from muscle biopsies of the vastus lateralis. Untreated MCI exhibited lower lipid-stimulated skeletal muscle mitochondrial respiration (State 3, ADP-stimulated) than both CH ( = .043) and MCI + med ( = .007) groups. MCI also exhibited poorer mitochondrial coupling control compared to CH ( = .014). RNA sequencing of skeletal muscle revealed unique differences in mitochondrial function and metabolism genes based on both MCI status (CH vs MCI) and medication treatment (MCI vs MCI + med). MCI + med modified over 600 skeletal muscle genes compared to MCI suggesting donepezil powerfully impacts the transcriptional profile of muscle. Overall, skeletal muscle mitochondrial respiration is altered in untreated MCI but normalized in donepezil-treated MCI participants while leak control is impaired regardless of medication status. These results provide evidence that mitochondrial changes occur in the early stages of AD, but are influenced by a common ad medicine. Further study of mitochondrial bioenergetics and the influence of transcriptional regulation in early ad is warranted.
阿尔茨海默病（AD）与胰岛素抵抗和低有氧能力有关，提示骨骼肌线粒体功能受损。然而，这在 AD 中尚未被直接测量。本研究（n=50）比较了认知健康的老年人（CH；n=24）与 AD 相关认知能力下降早期、轻度认知障碍（MCI；n=11）或接受 AD 药物多奈哌齐治疗的 MCI（MCI+med；n=15）的肌肉线粒体呼吸功能和基因表达谱。使用取自股外侧肌活检的透化肌纤维测量线粒体呼吸动力学。未经治疗的 MCI 与 CH（p=0.043）和 MCI+med（p=0.007）组相比，表现出较低的脂刺激骨骼肌线粒体呼吸（状态 3，ADP 刺激）。与 CH 相比，MCI 还表现出较差的线粒体偶联控制（p=0.014）。骨骼肌的 RNA 测序显示，基于 MCI 状态（CH 与 MCI）和药物治疗（MCI 与 MCI+med），线粒体功能和代谢基因存在独特差异。与 MCI 相比，MCI+med 改变了 600 多个骨骼肌基因，提示多奈哌齐强烈影响肌肉的转录谱。总体而言，未经治疗的 MCI 中骨骼肌线粒体呼吸发生改变，但在接受多奈哌齐治疗的 MCI 参与者中正常化，而无论药物状态如何，渗漏控制均受损。这些结果提供了证据表明，线粒体变化发生在 AD 的早期阶段，但受常见的 AD 药物影响。需要进一步研究早期 AD 中的线粒体生物能学和转录调节的影响。
