Decline in skeletal muscle mitochondrial function with aging in humans

Abstract

Cumulative mtDNA damage occurs in aging animals, and mtDNA mutations are reported to accelerate aging in mice. We determined whether aging results in increased DNA oxidative damage and reduced mtDNA abundance and mitochondrial function in skeletal muscle of human subjects. Studies performed in 146 healthy men and women aged 18 -89 yr demonstrated that mtDNA and mRNA abundance and mitochondrial ATP production all declined with advancing age. Abundance of mtDNA was positively related to mitochondrial ATP production rate, which in turn, was closely associated with aerobic capacity and glucose tolerance. The content of several mitochondrial proteins was reduced in older muscles, whereas the level of the oxidative DNA lesion, 8-oxo-deoxyguanosine, was increased, supporting the oxidative damage theory of aging. These results demonstrate that age-related muscle mitochondrial dysfunction is related to reduced mtDNA and muscle functional changes that are common in the elderly.sarcopenia ͉ mtDNA ͉ oxidative damage ͉ mRNA ͉ mitochondrial proteins M any structural and functional changes occur with age in skeletal muscle in a wide range of species. In Caenorhabditis elegans, muscle changes resembling those in humans precede neuronal changes, and are a determinant of morbidity (1). Age-related muscle wasting, muscle weakness, and reduced aerobic capacity result in many metabolic disorders and diminished physical performance in humans (2-4). Reduced muscle mitochondrial function could contribute to age-related muscle dysfunction and reduced aerobic capacity. Increased prevalence of mtDNA mutations (5, 6) and decreased mtDNA abundance (7, 8) have been proposed as underlying causes of mitochondrial dysfunction in aging. This finding is based on a hypothesis that cumulative oxidative damage could be the cause of aging (9).The rate of synthesis of contractile and mitochondrial proteins in human skeletal muscle declines with advancing age and may alter muscle metabolic capacity in older people (2-4). The activity of oxidative enzymes and content mRNA transcripts encoding mitochondrial proteins are also reduced in older muscles (3,7,10,11). Reduced synthesis and activity of specific proteins can alter muscle functions. The major functional role of mitochondria is ATP generation, but it remains unclear whether mitochondrial ATP production rate (MAPR) in skeletal muscle declines with age in humans. Previous studies that attempted to address this question are not in agreement, reporting that MAPR is either unchanged with age (12-16) or declines (17-19). These differences may arise from the use in some studies of inadequate sample sizes, failure to account for wide variations in physical fitness and diet, and the inclusion of subjects with metabolic abnormalities or undergoing surgical procedures at the time of analysis. Most of the previous studies examined discrete groups of younger and older people so it is unclear whether changes in mitochondria occur continuously across the adult life span or arise more rapidly later in life. We th...

Muscle strength mediates the relationship between mitochondrial energetics and walking performance

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“…Studies conducted in animal models and in humans have shown that skeletal muscle mitochondrial oxidative capacity declines with age (Conley et al ., 2000; Short et al ., 2005; Fleischman et al ., 2010; Peterson et al ., 2012), likely due to a decline in both total mitochondrial mass and decreased intrinsic mitochondrial functional capacity (Conley et al ., 2000). This steady decline of mitochondrial function with aging is believed to contribute to the progressive deterioration of muscle strength and quality (Metter et al ., 1999), as diminished energy production may constrain muscle performance, and dysfunctional mitochondria create oxidative stress that can damage proteins and mitochondrial DNA (Peterson et al ., 2012).…”

Pathophysiology of heart failure and frailty: a common inflammatory origin?

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Age modifies respiratory complex I and protein homeostasis in a muscle type‐specific manner

“…Therefore, muscle mitochondrial content and function are directly linked to muscle performance, metabolic disease risk, and quality of life (Conley et al ., 2000; Short et al ., 2005). Both in vivo and ex vivo approaches indicate that skeletal muscle mitochondrial function declines with age in both rodents and humans (Conley et al ., 2000; Amara et al ., 2007; Siegel et al ., 2012; Gouspillou et al ., 2014).…”