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.

Download full-text


Available from: Flemming Dela, Dec 04, 2014
18 Reads
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    The Journal of Physiology 06/2015; 593(17). DOI:10.1113/JP270211 · 5.04 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Mediators of Inflammation 06/2014; 2014(2):987017. DOI:10.1155/2014/987017 · 3.24 Impact Factor
  • Source
    • "Accordingly, a substantial body of evidence has accumulated over the past 3 decades in support of a role for oxidative damage to the mitochondrial respiratory chain and mitochondrial DNA in the determination of mammalian life span [26]. However, knockout and transgenic models do not support a clear role for mitochondrial oxidative stress or a vicious cycle of oxidative damage [26], which is in accordance with the observation that aged human skeletal muscle contains fully functional mitochondria and that the level of ROS may even be higher in young compared to aged muscle [27]. Evidently, more research is needed to elucidate the potential source(s) of ROS in aging and exercise. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Reactive oxygen species (ROS) are important signaling molecules with regulatory functions, and in young and adult organisms, the formation of ROS is increased during skeletal muscle contractions. However, ROS can be deleterious to cells when not sufficiently counterbalanced by the antioxidant system. Aging is associated with accumulation of oxidative damage to lipids, DNA and proteins. Given the pro-oxidant effect of skeletal muscle contractions, this effect of age could be a result of excessive ROS formation. We evaluated the effect of acute exercise on changes in blood redox state across the leg of young (23±1 years) and older (66±2 years) sedentary humans by measuring the whole blood concentration of the reduced (GSH) and oxidized (GSSG) form of the antioxidant glutathione. To assess the role of physical activity, lifelong physically active older subjects (62±2 years) were included. Exercise increased the venous concentration of GSSG in an intensity-dependent manner in young sedentary subjects, suggesting an exercise-induced increase in ROS formation. In contrast, venous GSSG levels remained unaltered during exercise in the older sedentary and active groups despite a higher skeletal muscle expression of the superoxide generating enzyme NADPH oxidase. Arterial concentration of GSH and expression of antioxidant enzymes in skeletal muscle of older active subjects was found to be increased. The potential impairment in exercise-induced ROS formation may be an important mechanism underlying skeletal muscle and vascular dysfunction with sedentary aging. Lifelong physical activity up-regulates antioxidant systems which may be one of the mechanisms underlying the lack of exercise-induced increase in GSSG.
    Free Radical Biology and Medicine 05/2014; 73. DOI:10.1016/j.freeradbiomed.2014.05.008 · 5.74 Impact Factor
Show more