Oxidative capacity and ageing in human muscle

This study determined the decline in oxidative capacity per volume of human vastus lateralis muscle between nine adult (mean age 38.8 years) and 40 elderly (mean age 68.8 years) human subjects (age range 25-80 years). We based our oxidative capacity estimates on the kinetics of changes in creatine phosphate content ([PCr]) during recovery from exercise as measured by 31P magnetic resonance (MR) spectroscopy. A matched muscle biopsy sample permitted determination of mitochondrial volume density and the contribution of the loss of mitochondrial content to the decline in oxidative capacity with age. The maximal oxidative phosphorylation rate or oxidative capacity was estimated from the PCr recovery rate constant (kPCr) and the [PCr] in accordance with a simple electrical circuit model of mitochondrial respiratory control. Oxidative capacity was 50 % lower in the elderly vs. the adult group (0.61 ± 0.04 vs. 1.16 ± 0.147 mM ATP s−1). Mitochondrial volume density was significantly lower in elderly compared with adult muscle (2.9 ± 0.15 vs. 3.6 ± 0.11 %). In addition, the oxidative capacity per mitochondrial volume (0.22 ± 0.042 vs. 0.32 ± 0.015 mM ATP (s %)−1) was reduced in elderly vs. adult subjects. This study showed that elderly subjects had nearly 50 % lower oxidative capacity per volume of muscle than adult subjects. The cellular basis of this drop was a reduction in mitochondrial content, as well as a lower oxidative capacity of the mitochondria with age. Muscle and whole body maximal aerobic performance decline with age in humans (Buskirk & Hodgson, 1987; Brooks & Faulkner, 1994). The loss of muscle mass is an important contributor to this decline (Proctor & Joyner, 1997), but the role of oxidative capacity per muscle mass is less clear. Age-related changes in volume-specific oxidative capacity have been inferred from both in vitro and in vivo measurements of muscle oxidative properties. For example, a decline in marker enzyme activity in muscle biopsies and a slower recovery rate from exercise indicate a reduced capacity for oxidative phosphorylation in elderly muscle (Coggan et al. 1993; McCully et al. 1993; Papa, 1996). However, it is unclear how these relative measures of aerobic properties relate to the muscle's capacity for oxidative phosphorylation. What is needed is a quantitative measure of oxidative capacity to determine the contribution of muscle properties to the decline in maximal oxygen consumption and aerobic performance with age. Two tools have the potential for allowing a determination of muscle oxidative capacity in vivo. First are magnetic resonance (MR) methods that make possible non-invasive assessment of the change in muscle energetics in vivo. These methods allow us to measure changes in metabolites, such as creatine phosphate (PCr), during muscle activity. The greater change in [PCr] for a given steady-state exercise rate normalized to muscle mass in the elderly indicates a lower muscle oxidative capacity compared with the young (Coggan et al. 1993; McCully et al. 1993). We can now use the recovery of [PCr] after exercise to quantify the change in oxidative properties of muscle with age (Blei et al. 1993; Walter et al. 1997). The second tool allowing us to determine oxidative capacity in muscle is the model of the control of oxidative phosphorylation presented by Meyer et al. (Meyer, 1988, 1989; Paganini et al. 1997). These workers have shown that a simple electrical circuit model links the change in [PCr] with exercise to the mitochondrial oxidative phosphorylation rate. Human and rodent studies have shown that the rate constant describing [PCr] recovery following exercise (kPCr) is proportional to the oxidative enzyme activity of muscle (McCully et al. 1993; Paganini et al. 1997). At full PCr depletion (Δ[PCr]), the model predicts that the mitochondria should be working at their oxidative capacity. Thus the PCr level and the dynamics following exercise provide a means of estimating muscle oxidative capacity in vivo. The purpose of this study was to determine the oxidative capacity of muscle and how it differs between adult and elderly groups. We evaluated muscle properties using 31P MR spectroscopy during electrical stimulation and recovery of the vastus lateralis muscle. Specifically, the [PCr] dynamics during recovery was used to quantify the kPCr of each subject and, along with [PCr] at rest ([PCr]rest), was used to estimate oxidative capacity. This estimate was compared with an independent method based on mitochondrial volume density determined from muscle biopsies taken at the site of the MR acquisition. Our main finding was a 50 % reduction in oxidative capacity between the adult and elderly groups, half of which was due to reduced mitochondrial volume density and the remaining half to reduced mitochondrial function.