Mild cognitive impairment and donepezil impact mitochondrial respiratory capacity in skeletal muscle
Function | September 2, 2021
Morris JK, McCoin CS, Fuller KN, John CS, Wilkins HM, Green ZD, Wang X, Sharma P, Burns JM, Vidoni ED, Mahnken JD, Shankar K, Swerdlow RH and Thyfault JP
Alzheimer’s Disease (AD) associates with insulin resistance and low aerobic capacity suggestive of impaired skeletal muscle mitochondrial function. However, direct measures of muscle mitochondrial function have not been performed in AD. This study (n = 50) compared skeletal muscle mitochondrial respiratory function and gene expression profiling in cognitively healthy older adults (CH; n = 24) to 26 individuals in the earliest phase of AD-related cognitive decline, mild cognitive impairment (MCI; n = 11) or MCI taking an AD medication, donepezil (MCI + med; n = 15). Mitochondrial respiratory kinetics were measured in permeabilized muscle fibers from skeletal muscle biopsies of the vastus lateralis. Untreated MCI subjects exhibited lower lipid-stimulated skeletal muscle mitochondrial respiration (State 3, ADP-stimulated) than both CH (P = 0.043) and MCI + med (P = 0.007) groups. MCI also exhibited poorer mitochondrial coupling control compared to CH (P = 0.014). 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 donepezeil powerfully impacts the transcriptional profile of skeletal muscle. Overall, skeletal muscle mitochondrial respiration is altered in untreated MCI but normalized in donepezil-treated MCI participants while mitochondrial leak control is impaired regardless of medication status. These results provide further evidence that skeletal muscle mitochondrial changes occur in the very early stages of AD, but is likely influenced by a common AD medicine. Further study of mitochondrial bioenergetics and the influence of transcriptional regulation in early AD is warranted.