Mild cognitive impairment is associated with skeletal muscle mitochondrial deficits

Author:

Morris Jill K.ORCID,McCoin Colin S.,Fuller Kelly N.,John Casey S.,Wilkins Heather M.,Wang Xiaowan,Sharma Palash,Burns Jeffrey M.,Vidoni Eric D.,Mahnken Jonathan D.,Swerdlow Russell H.,Thyfault John P.

Abstract

AbstractAlzheimer’s Disease (AD) is associated with insulin resistance and low cardiorespiratory fitness, suggestive of impaired skeletal muscle mitochondrial function. We examined if individuals with Mild Cognitive Impairment (MCI), the earliest phase of AD-related cognitive decline, exhibit reduced skeletal muscle mitochondrial function, and if AD medication impacted outcomes. We present data from 50 individuals, including cognitively healthy older adults (CH; n=24) 60+ years of age and clinically diagnosed MCI subjects (n=26). MCI subjects were sub-divided into two groups; no AD medication (MCI; n=11), or AD medication treated (MCI+med; n=15). A skeletal muscle biopsy (vastus lateralis) was obtained and mitochondrial respiratory kinetics was measured in permeabilized muscle fibers. MCI subjects exhibited lower lipid-stimulated skeletal muscle mitochondrial respiration (State 3, ADP-stimulated) than both CH individuals (p=0.043) and medication-treated MCI subjects (p=0.006). MCI also exhibited poorer mitochondrial coupling control compared to CH subjects (p=0.014), while MCI+med and CH subjects did not differ. Compared to CH individuals, skeletal muscle mitochondrial leak control ratio was lower for the MCI+med group (p=0.008) and trended lower for non-medicated MCI (p=0.06), which suggests greater mitochondrial uncoupling in MCI. Skeletal muscle mitochondrial respiration is impaired in untreated MCI but normalized in medication-treated MCI participants while mitochondrial leak control is impaired regardless of medication status. These results provide further evidence that systemic mitochondrial deficits occur in the very early stages of AD, and that mitochondrial function is partially influenced by AD medication. Further analysis for a role of muscle mitochondria in the progression of early AD is warranted.

Publisher

Cold Spring Harbor Laboratory

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