Hutter E, Skovbro M, Lener B et al.Oxidative stress and mitochondrial impairment can be separated from lipofuscin accumulation in aged human skeletal muscle. Aging Cell 6:245-256

Department for Molecular and Cellular Biology, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, 6020 Innsbruck, Austria.
Aging Cell (Impact Factor: 6.34). 05/2007; 6(2):245-56. DOI: 10.1111/j.1474-9726.2007.00282.x
Source: PubMed


According to the free radical theory of aging, reactive oxygen species (ROS) act as a driving force of the aging process, and it is generally believed that mitochondrial dysfunction is a major source of increased oxidative stress in tissues with high content of mitochondria, such as muscle or brain. However, recent experiments in mouse models of premature aging have questioned the role of mitochondrial ROS production in premature aging. To address the role of mitochondrial impairment and ROS production for aging in human muscles, we have analyzed mitochondrial properties in muscle fibres isolated from the vastus lateralis of young and elderly donors. Mitochondrial respiratory functions were addressed by high-resolution respirometry, and ROS production was analyzed by in situ staining with the redox-sensitive dye dihydroethidium. We found that aged human skeletal muscles contain fully functional mitochondria and that the level of ROS production is higher in young compared to aged muscle. Accordingly, we could not find any increase in oxidative modification of proteins in muscle from elderly donors. However, the accumulation of lipofuscin was identified as a robust marker of human muscle aging. The data support a model, where ROS-induced molecular damage is continuously removed, preventing the accumulation of dysfunctional mitochondria despite ongoing ROS production.

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Available from: Flemming Dela, Dec 04, 2014
    • "However, only a few human studies have investigated whether ROS production is increased with age and presently there is a lack of consensus. Accordingly, both an increase (Capel et al., 2005), no change (Tonkonogi et al., 2003) and a decrease (Hutter et al., 2007; Ghosh et al., 2011) in ROS production have been shown with age. Also, in animal data there is no consensus (Bejma & Ji, 1999; Drew et al., 2003; Capel et al., 2004). "
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    ABSTRACT: Mitochondrial dysfunction, defined as increased oxidative stress and lower capacity for energy production, may be seen with aging and may cause frailty, or it could be that it is secondary to physical inactivity. We studied the effect of two weeks of one-leg immobilization followed by six weeks of supervised cycle training on mitochondrial function in 17 young (23 ± 1 years, mean ± SEM) and 15 older (68 ± 1 years) healthy men. Submaximal hydrogen peroxide (H2 O2 ) emission and respiration were measured simultaneously at a predefined membrane potential in isolated mitochondria from skeletal muscle using two protocols pyruvate+malate (PM) and succinate+rotenone (SR). This allowed measurement of leak and ATP generating respiration from which the coupling efficiency can be calculated. Protein content of the antioxidants manganese superoxide dismuthase (MnSOD), CuZn-superoxide dismuthase (CuZnSOD), catalase and gluthathione peroxidase 1 (GPX1) were measured by Western Blotting. Immobilization decreased ATP generating respiration using PM and increased H2 O2 emission using both PM and SR similarly in young and older men. Both were restored to baseline after the training period. Furthermore, MnSOD and catalase content increased with endurance training. The young men had a higher leak respiration at inclusion using PM and a higher membrane potential in state 3 using both substrate combinations. Collectively, this study supports the notion that increased mitochondrial ROS mediates the detrimental effects seen after physical inactivity. Age on the other hand was not associated with impairments in antioxidant protein levels, mitochondrial respiration or H2 O2 emission using either protocol. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jun 2015 · The Journal of Physiology
    • "c o m / l o c a t e / e x p g e r o literature. Lower oxidative capacity with aging is found in some (Conley et al., 2000; McCully et al., 1991, 1993; Petersen et al., 2003; Short et al., 2005; Taylor et al., 1997; Tonkonogi et al., 2003) but not all studies (Barrientos et al., 1996; Brierly et al., 1997; Chretien et al., 1998; Hutter et al., 2007; Kent-Braun and Ng, 2000; Lanza et al., 2008; Rasmussen et al., 2003). However, the level of physical activity is a major confounding factor in studies examining skeletal muscle mitochondrial oxidative capacity. "
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    ABSTRACT: Physical inactivity affects human skeletal muscle mitochondrial oxidative capacity but the influence of aging combined with physical inactivity is not known. This study investigates the effect of two weeks of immobilization followed by six weeks of supervised cycle training on muscle oxidative capacity in 17 young (23±1years) and 15 elderly (68±1years) healthy men. We applied high-resolution respirometry in permeabilized fibers from muscle biopsies at inclusion after immobilization and training. Furthermore, protein content of mitochondrial complexes I-V, mitochondrial heat shock protein 70 (mtHSP70) and voltage dependent anion channel (VDAC) were measured in skeletal muscle by Western blotting. The elderly men had lower content of complexes I-V and mtHSP70 but similar respiratory capacity and content of VDAC compared to the young. In both groups the respiratory capacity and protein content of VDAC, mtHSP70 and complexes I, II, IV and V decreased with immobilization and increased with retraining. Moreover, there was no overall difference in the response between the groups. When the intrinsic mitochondrial capacity was evaluated by normalizing respiration to citrate synthase activity, the respiratory differences with immobilization and training disappeared. In conclusion, aging is not associated with a decrease in muscle respiratory capacity in spite of lower complexes I-V and mtHSP70 protein content. Furthermore, immobilization decreased and aerobic training increased the respiratory capacity and protein contents of complexes I-V, mtHSP70 and VDAC similarly in the two groups. This suggests that inactivity and training alter mitochondrial biogenesis equally in young and elderly men.
    No preview · Article · Sep 2014 · Experimental Gerontology
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    • "The mitochondrial function impairment in skeletal muscle is one of the physiological limitations of aging [1]. However, there is a considerable variability of aging impact on mitochondrial function [2] [3] [4] [5] [6]. Sarcopenia and muscle fatigability in response to aging are associated with the increase of both the reactive oxygen species (ROS) production and the mitochondrial apoptotic susceptibility, as well as the decrease of transcriptional drive for mitochondrial biogenesis [3]. "
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    ABSTRACT: The present study investigated the effects of running at 0.8 or 1.2 km/h on inflammatory proteins (i.e., protein levels of TNF- α , IL-1 β , and NF- κ B) and metabolic proteins (i.e., protein levels of SIRT-1 and PGC-1 α , and AMPK phosphorylation) in quadriceps of rats. Male Wistar rats at 3 (young) and 18 months (middle-aged rats) of age were divided into nonexercised (NE) and exercised at 0.8 or 1.2 km/h. The rats were trained on treadmill, 50 min per day, 5 days per week, during 8 weeks. Forty-eight hours after the last training session, muscles were removed, homogenized, and analyzed using biochemical and western blot techniques. Our results showed that: (a) running at 0.8 km/h decreased the inflammatory proteins and increased the metabolic proteins compared with NE rats; (b) these responses were lower for the inflammatory proteins and higher for the metabolic proteins in young rats compared with middle-aged rats; (c) running at 1.2 km/h decreased the inflammatory proteins and increased the metabolic proteins compared with 0.8 km/h; (d) these responses were similar between young and middle-aged rats when trained at 1.2 km. In summary, the age-related increases in inflammatory proteins, and the age-related declines in metabolic proteins can be reversed and largely improved by treadmill training.
    Full-text · Article · Jun 2014 · Mediators of Inflammation
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