Skeletal muscle mitochondria and aging: a review

Abstract

Aging is characterized by a progressive loss of muscle mass and muscle strength. Declines in skeletal muscle mitochondria are thought to play a primary role in this process. Mitochondria are the major producers of reactive oxygen species, which damage DNA, proteins, and lipids if not rapidly quenched. Animal and human studies typically show that skeletal muscle mitochondria are altered with aging, including increased mutations in mitochondrial DNA, decreased activity of some mitochondrial enzymes, altered respiration with reduced maximal capacity at least in sedentary individuals, and reduced total mitochondrial content with increased morphological changes. However, there has been much controversy over measurements of mitochondrial energy production, which may largely be explained by differences in approach and by whether physical activity is controlled for. These changes may in turn alter mitochondrial dynamics, such as fusion and fission rates, and mitochondrially induced apoptosis, which may also lead to net muscle fiber loss and age-related sarcopenia. Fortunately, strategies such as exercise and caloric restriction that reduce oxidative damage also improve mitochondrial function. While these strategies may not completely prevent the primary effects of aging, they may help to attenuate the rate of decline.

Figures

Figure 1

This cartoon describes the changes in skeletal muscle with aging on the right side of the figure. Both the mass and function of skeletal muscle are decreased in elderly people. Furthermore, at the mitochondrial level, the number of mitochondria is decreased in parallel with changes in mitochondrial morphology. Mitochondrial DNA, oxidative capacity, biogenesis, and autophagy are all decreased in conjunction with an increased number of DNA mutations and increased levels of apoptosis. Finally, oxidative stress is increased in the muscles of elderly people in association with cellular lipid, protein, and DNA damage. The bottom left of the cartoon shows that exercise, caloric restriction, caloric restriction mimetics, and antioxidants can all delay the aging of skeletal muscle.

Figure 2

Mitochondrial processes are both static (a) and dynamic (b). (a) depicts the classical movement of electrons along complexes I–IV embedded in the inner mitochondrial membrane with the generation of a proton gradient (membrane potential). The proton gradient causes hydrogen ions to flow back into the mitochondrial matrix via complex V (ATP synthase), producing ATP in the process. (b) depicts the processes of mitochondrial fusion and fission. Mitochondria can undergo constriction and division (1), mediated by Drp1, which bonds and localizes to the constriction site via an interaction with the receptor-like protein Fis1 (2). During fusion, a tether of the Mfn1/2 to collateral mitochondrial Mfn1/2 conjoins the outer membranes. Opa1, an inner membrane GTPase protein, facilitates the fusion of the inner membrane, cristae formation, and unifying of compartments.

Figure 3

The electron transport system (ETS) of the inner mitochondrial membrane is the primary site of reactive oxygen species (ROS) production and therefore the main source of oxidative stress (damage to proteins, lipids, and DNA) in the mitochondria and in the cell. Free radical superoxide anions (O2 ∙−) are generated when electrons are donated from complexes I and III of the ETS to O2 instead of the appropriate ETS subunit. 2–4% of total oxygen consumption may go toward the production of ROS instead of energy as ATP. Scavenging enzymes represent an important mitochondrial defense mechanism against oxidative stress by neutralizing O2 ∙− within the mitochondrial matrix (superoxide dismutase; MnSOD = SOD2) and catalyzing the reduction of mitochondrial SOD2-generated H2O2 to nontoxic H2O in the mitochondria and the cell (glutathione peroxidase and catalase). Mitochondria in young muscle (a) are numerous and efficient. With age (b), muscle mitochondria become less numerous and seem to develop impaired function associated with reduced oxidative capacity. Through lifestyle changes such as exercise, and caloric restriction, and caloric restriction mimetics, we hypothesize that antioxidative enzymes are upregulated, and that most of the above impairments in aged muscle may be improved (c).