Mild mitochondrial uncoupling impacts cellular aging in human muscles in vivo

Abstract

Faster aging is predicted in more active tissues and animals because of greater reactive oxygen species generation. Yet age-related cell loss is greater in less active cell types, such as type II muscle fibers. Mitochondrial uncoupling has been proposed as a mechanism that reduces reactive oxygen species production and could account for this paradox between longevity and activity. We distinguished these hypotheses by using innovative optical and magnetic resonance spectroscopic methods applied to noninvasively measured ATP synthesis and O 2 uptake in vivo in human muscle. Here we show that mitochondrial function is unchanged with age in mildly uncoupled tibialis anterior muscle (75% type I) despite a high respiratory rate in adults. In contrast, substantial uncoupling and loss of cellular [ATP] indicative of mitochondrial dysfunction with age was found in the lower respiring and well coupled first dorsal interosseus (43-50% type II) of the same subjects. These results reject respiration rate as the sole factor impacting the tempo of cellular aging. Instead, they support mild uncoupling as a mechanism protecting mitochondrial function and contributing to the paradoxical longevity of the most active muscle fibers. magnetic resonance spectroscopy ͉ optical spectroscopy ͉ oxidative phosphorylation T he rate-of-living hypothesis proposes that higher rates of oxidative metabolism cause an increased production of reactive oxygen species (ROS) (1), leading to oxidative damage and mitochondrial dysfunction with age. However, mice with the lowest resting respiration rate have been shown to have the shortest longevity (2). Similarly, isolated muscle fibers show greater generation of ROS in type II fibers (3), which have the lowest oxidative capacity and chronic activity levels. This fiber type also has the shortest longevity and is the first to be lost with age (4). Thus, the tempo of aging appears to vary among mice and muscle fiber types but in an opposite manner than predicted by the rate-of-living hypothesis, with the least active having the shortest longevity.A physiological mechanism that could account for this paradox is mild mitochondrial uncoupling, which has been proposed to ameliorate ROS production by reducing reverse electron flow and superoxide generation (5). Consistent with this prediction are findings in mice with high respiration rates that showed elevated proton leak in isolated muscle mitochondria as a result of activation of the adenine nucleotide translocator and uncoupling protein 3. Mild uncoupling resulting from activation of these mitochondrial factors in type I muscle fibers could reduce ROS production, protect mitochondria from damage, and account for the longevity of this fiber type with age. A number of studies have provided evidence of mild uncoupling in human muscles (6, 7) but have not tested whether this uncoupling protects against mitochondrial dysfunction and cellular aging.New methods permit measurement of mitochondrial coupling in vivo by using a combination of noninvasive spectroscopi...

Comparison of measuring energy metabolism by different 31P‐magnetic resonance spectroscopy techniques in resting, ischemic, and exercising muscle

“…In the absence of oxygen, the rate of PCr breakdown compensates for lacking oxidative phosphorylation and has been suggested as a measure of net aerobic ATP turnover in the resting state (8). As to the relationship between resting activity and maximal capacity, it is of note that oxygen consumption and ATP need have been shown to be diminished in skeletal muscle of elderly subjects (20), known to have lower mitochondrial function (29). These data are in line with the present findings of lower ATP synthesis in humans with delayed PCr recovery kinetics.…”

“…Glycolysis, which could contribute to fATP, is assumed to operate at low rates in the resting state (20). Although net glycolytic ATP production cannot explain the higher values found with saturation transfer measurements, glycolytic ATP forming reaction might still play an important role.…”

“…2c) was used to calculate Q ¼ dPCr/dt based on (20). The anaerobic contribution to net resting ATP turnover L was estimated using pH variation according to Kemp and Radda (8), assuming no efflux of protons in the ischemic state, using the equation:…”

Mitochondria and aging: A role for the mitochondrial transition pore?

“…This is in accordance with data from Delaney et al. (2013) showing in yeast that cells with the lowest mitochondrial membrane potential have the longest subsequent replicative lifespan, but also with the demonstration that mild uncoupling protects mitochondrial function and contributes to the longevity of the most active human muscle fibers (Amara et al., 2007). A possible reason for this protective effect is the prevention of ROS production which is a well‐known consequence of a mild drop in membrane potential (Skulachev, 1998).…”

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). In addition to their role as the primary site of ATP production in most cells, mitochondria are also critical for cell health and function due to their role in controlling apoptosis, calcium buffering, redox signaling, differentiation, and growth.…”