Mitochondria are the cell's power plants, swarming in bacteria-like herds to create chemical energy stores. They bear their own DNA, distinct from that in the cell nucleus. This mitochondrial DNA can become damaged in aging and some forms of this damage create harmful, malfunctioning mitochondria that overtake their cell and cause it to export damaging reactive compounds into surrounding tissues. One possible cause of this mitochondrial DNA damage is the fact that generating chemical energy stores results in the creation of reactive oxygen species (ROS) as a byproduct. This flux of ROS influences cellular activities in many ways, such as by spurring greater or lesser levels of housekeeping activity, and by causing damage directly through reactions with important molecular machinery.
In past years researchers have demonstrated benefits resulting from the delivery of targeted antioxidant compounds to the mitochondria, with the assumption that they produce benefits by soaking up more of the ROS before they can cause harm. One approach here is to use genetic engineering to increase levels of the natural antioxidant catalase: some studies have shown extension of life in mice via this method, while others have not. The delivery of artificial mitochondrially targeted antioxidants as drugs has been studied more closely, in comparison, and the results there are generally more consistent, showing small effects on life span and enough of a benefit to health for some conditions to make it worth building treatments.
Age-related muscle weakness has major adverse consequences on quality of life, increasing the risk of falls, fractures, and movement impairments. Albeit an increased oxidative state has been shown to contribute to age-dependent reduction in skeletal muscle function, little is known about the mechanisms connecting oxidation and muscle weakness. We show here that genetically enhancing mitochondrial antioxidant activity causes improved skeletal muscle function and voluntary exercise in aged mice.
Here we tested the effects of increased mitochondrial antioxidant activity on age-dependent skeletal muscle dysfunction using transgenic mice with targeted overexpression of the human catalase gene to mitochondria (MCat mice). Aged MCat mice exhibited improved voluntary exercise, increased skeletal muscle specific force and tetanic Ca2+ transients, decreased intracellular Ca2+ leak and increased sarcoplasmic reticulum (SR) Ca2+ load compared with age-matched wild type (WT) littermates.
Overall, these data indicate a direct role for mitochondrial free radicals in promoting the pathological intracellular Ca2+ leak that underlies age-dependent loss of skeletal muscle function. This study harbors implications for the development of novel therapeutic strategies, including mitochondria-targeted antioxidants for treatment of mitochondrial myopathies and other healthspan-limiting disorders.