Mild Cognitive Impairment and Donepezil Impact Mitochondrial Respiratory Capacity in Skeletal Muscle

Abstract

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.

Infection and chronic disease activate a brain-muscle signaling axis that regulates muscle performance

“…Although the connections between AD and sarcopenia are poorly understood, AD and musculoskeletal aging are associated with an overlapping set of differentially expressed genes that regulate mitochondrial function (Giannos et al, 2022). In addition, skeletal muscle mitochondria from individuals in the early phases of AD showed reduced respiratory kinetics and poor control of mitochondria coupling (Morris et al, 2021). Chronic neuroinflammation in AD correlates with reduced mitochondrial function in skeletal muscle, and our in silico analysis argues circulating IL-6 levels are increased in AD patients.…”

Can the Energetic Profile of Skeletal Muscle Predict Risk of Cognitive Impairment?

“…Morris et al sought to assess mitochondrial capacity in skeletal muscle of patients with early stages of cognitive decline and determine if respiratory function was associated with genetic risk (Apolipoprotein ε4; APOE4 ) or non-genetic risk factors (overweight/obesity, physical activity, and so on). 1 Mitochondrial respiratory capacity was assessed in fiber bundles from skeletal muscle biopsies from patients with mild-cognitive impairment (MCI, ( n = 11)) or MCI patients treated with donepezil (MCI + med, ( n = 15)) or cognitive healthy age-matched patients (CH, n = 24). Donepezil is a cholinesterase inhibitor that appears to improve memory and awareness and is prescribed to patients suffering from dementia.…”

“…MCI is the earliest clinical stage of ad , and represents a possible window for therapeutic intervention that could prevent or attenuate further symptom development. 1 Unfortunately, identification of ad in the earliest stages remains a challenge, thus making timing of an intervention more difficult. Thus, if patients with MCI or ad have a unique bioenergetic signature in their skeletal muscle tissue, it might be possible to use that as a biomarker for early identification of patients providing an improved window for therapeutic intervention.…”

“…Overall, this contribution is incredibly important to the field, as it hopefully will encourage an innovative scientific movement toward early diagnosis and development of reliable biomarkers that improve the possibility of intervention . 1 In conclusion, the study by Morris et al was difficult in scope, but with the application of rigorous methods and a well-designed approach, the authors have provided the field critical data that will provide a meaningful road map moving forward towards developing approaches for patients that are at risk for developing MCI or ad . 1 …”

“… 1 In conclusion, the study by Morris et al was difficult in scope, but with the application of rigorous methods and a well-designed approach, the authors have provided the field critical data that will provide a meaningful road map moving forward towards developing approaches for patients that are at risk for developing MCI or ad . 1 …”