Mitochondria in Muscle Aging and Sarcopenia
This review paper takes a look at some of what is known of the contribution of mitochondrial dysfunction to age-related loss of muscle mass and strength, progressing towards the condition known as sarcopenia. The hundreds of mitochondria packed into every cell act as power plants; these evolved descendants of symbiotic bacteria are responsible for, among many other things, generating chemical energy stores to power cellular operations. This process also produces potentially disruptive reactive oxygen species as a byproduct, but the structures most likely to take the brunt of that disruption are the mitochondria themselves. Mitochondrial damage is important in the aging process, producing a growing population of dysfunctional cells that export harmful reactive molecules into surrounding tissues, giving rise to damaged proteins that contribute to a range of age-related conditions. Declining energy store production is also a significant problem in tissues that need greater amounts of energy to function and maintain themselves, such as muscles:
Loss of muscle mass and muscle wasting are clinical symptoms associated with many chronic diseases as well as with the aging process. The loss of muscle mass accompanied by a decrease in muscle strength and resistance which occurs in the elderly is termed sarcopenia. In the population over 65 years of age, this decay in muscle function is particularly associated with increased dependence, frailty, and mortality. In fact, sarcopenia is the main cause of disability among the elderly. Among the mechanisms that contribute to sarcopenia have been described the decrease in physical activity, the decrease in anabolic hormones, and an increase in proinflammatory cytokines as well as the increase in catabolic factors. Further, recent studies have also identified that not only mitochondrial metabolic dysfunction but mitochondrial dynamics and mitochondrial calcium uptake too could be involved in the degeneration of skeletal muscle mass. A growing body of evidence suggests that muscle quality plays a systemic role in the aging process. Thus, it has become apparent that mitochondrial status in muscle cells could be a driver of whole body physiology and organism aging.
Reactive oxygen species (ROS) are produced in the mitochondria as a byproduct of an inefficient transfer of electrons through the electron transport chain (ETC). During the aging process, ROS production increases as well as mitochondrial damage and dysfunction. These phenomena have also been observed in age-associated diseases. In fact, it is supposed that the observed increase in ROS is derived from a decline in mitochondrial function. Interestingly, in flies, the development of genetic sensors which can be targeted specifically to a tissue or to an organelle within the cell is helping to reveal which tissues are subject to redox dysregulation during aging. Increased production of ROS in aged and age-related phenotypes has also been observed to be accompanied by alterations in mitochondrial DNA (mtDNA) quality and quantity. It has been proposed that increases in ROS could easily target the mtDNA which lacks histone protection. Furthermore, it is argued that with aging, DNA repair mechanisms efficiency decline and could lead to mutations in mtDNA.
Consistent with the paradigm, in mice, it has been found that ROS production is increased in aged muscles and directly affects the complex V (ATP synthase) of the ETC, oxidizing, thereby preventing the synthesis of ATP by the oxidized protein. One possible consequence of this process is that the damaged mtDNA promotes the biogenesis of damaged mitochondria, in turn producing more ROS, enabling a vicious cycle to continue. Contrasting these results, recent deep sequencing of mitochondrial genomes in mice suggests, otherwise, that mutations in the mtDNA arise from replication errors during early life. Increased ROS species in the cell have also been associated with diminished ROS scavengers activities during aging. Interestingly, recent evidence has demonstrated that genetic manipulation of mitochondrial antioxidants, given by the overexpression of human mitochondrial catalase in old mice, protects from oxidative damage and age-associated mitochondrial dysfunction, together with protecting from energy metabolism diminution in age. Several questions remain open regarding the behavior of ROS during organism and muscle aging. For example, when in lifespan do ROS first appear in the muscle? Or which concentrations of ROS are required to alter the gene and protein networks that ensure mitochondria and muscle quality functions? These are still matters to be addressed.