Skeletal muscle is versatile in its choice of fuels for energy need. It mainly derived from glucose during post-prandial state but switch to fat as its main fuel in the fasted state. Amino acids are not a major source of fuel except following high protein meals and on prolonged starvation. Mitochondria are the organelle responsible for converting oxidized macronutrient fuels to adenosine triphosphate (ATP) which is the obligatory energy source for all cellular functions. Insulin is a key regulator of muscle mitochondrial biogenesis and function. Insulin deficiency and insulin resistance are associated with inefficient mitochondrial coupling and increased emission of reactive oxygen species (ROS). ROS also causes irreversible damage to mitochondrial proteins and accelerates protein degradation. Insulin deficiency therefore causes reduced mitochondrial protein synthesis and increased proteomic content. Similarly sedentary people mitochondrial protein synthesis and protein content decline with age with detrimental effects on oxidative capacity and mortality. However, these age-related decline in mitochondrial content and function are almost completely corrected by vigorous aerobic exercise training. Exercise training increases not only mitochondrial gene transcripts but also translational machinery and synthesis of new proteins thus enhancing oxidizing capacity. Aerobic exercise training also reduces muscle oxidative stress and oxidative damage to protein. Maintaining mitochondrial function is critical for maintaining exercise capacity which is a major predictor of life span and health span.