Reduced Mitochondrial Content, Elevated Reactive Oxygen Species, and Modulation by Denervation in Skeletal Muscle of Prefrail or Frail Elderly Women

Abstract

Denervation and mitochondrial impairment are implicated in age-related skeletal muscle atrophy and may play a role in physical frailty. We recently showed that denervation modulates muscle mitochondrial function in octogenarian men, but this has not been examined in elderly women. On this basis, we tested the hypothesis that denervation plays a modulating role in mitochondrial impairment in skeletal muscle from prefrail or frail elderly (FE) women. Mitochondrial respiratory capacity and reactive oxygen species emission were examined in permeabilized myofibers obtained from vastus lateralis muscle biopsies from FE and young inactive women. Muscle respiratory capacity was reduced in proportion to a reduction in a mitochondrial marker protein in FE, and mitochondrial reactive oxygen species emission was elevated in FE versus young inactive group. Consistent with a significant accumulation of neural cell adhesion molecule-positive muscle fibers in FE (indicative of denervation), a 50% reduction in reactive oxygen species production after pharmacologically inhibiting the denervation-mediated reactive oxygen species response in FE women suggests a significant modulation of mitochondrial function by denervation. In conclusion, our data support the hypothesis that denervation plays a modulating role in skeletal muscle mitochondrial function in FE women, suggesting therapeutic strategies in advanced age should focus on the causes and treatment of denervation.

Rehabilitative Impact of Exercise Training on Human Skeletal Muscle Transcriptional Programs in Parkinson’s Disease

“…Both SCN5A (voltage-gated sodium channel 5A, known also as Na v 1.5) and NCAM (neural cell adhesion molecule) were among the top 50 genes grouped into LV16. These factors are often assessed as markers of denervation in adult skeletal muscle (Rowan et al, 2012;Sekiguchi et al, 2012;Hendrickse et al, 2018;Sonjak et al, 2019). The reduction in expression of these transcripts following RT supports our laboratory's previous findings (Kelly et al, 2018a) and provides direction toward other possible targets for assessment in muscle denervation-reinnervation cycling, including ERBB3 (Erb-B2 receptor tyrosine kinase 3) (Morano et al, 2018) and MAGED1 (melanoma antigen gene family D1) (Magnusson et al, 2005).…”

Intramuscular short‐chain acylcarnitines in elderly people are decreased in (pre‐)frail females, but not in males

“…Taken this all together, a picture emerges that possibly suggests a collapse of skeletal muscle mitochondria in the (pre-) frail females. 32,34,35 While this notion needs to be confirmed by other techniques, such as for example electron-microscopy or biochemical analyses, for which we regretfully did not have enough sample available, it may be that impaired mitochondrial function could be a cause, rather than a consequence, of the altered intramuscular carnitine status in the (pre-)frail females.…”

Kynurenines link chronic inflammation to functional decline and physical frailty

“…In this study, we saw increased partial denervation in older IL-10 tm mice compared with controls — a result that aligns with our previous work showing distal axon degeneration in the aging peripheral motor nerve system ( 38 ). A recent study in humans has reported increases in markers of denervation in the vastus lateralis muscle of frail elderly females compared with those of young inactive females ( 40 ). Therefore, we propose that the motor nerve degeneration is responsible for the muscle and myofiber atrophy seen in this study.…”