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Abstract
<p class="first" id="d3225624e91">Mitochondrial health is an important mediator of
cellular function across a range
of tissues, and as a result contributes to whole-body vitality in health and disease.
Our understanding of the regulation and function of these organelles is of great interest
to scientists and clinicians across many disciplines within our healthcare system.
Skeletal muscle is a useful model tissue for the study of mitochondrial adaptations
because of its mass and contribution to whole body metabolism. The remarkable plasticity
of mitochondria allows them to adjust their volume, structure and capacity under conditions
such as exercise, which is useful or improving metabolic health in individuals with
various diseases and/or advancing age. Mitochondria exist within muscle as a functional
reticulum which is maintained by dynamic processes of biogenesis and fusion, and is
balanced by opposing processes of fission and mitophagy. The sophisticated coordination
of these events is incompletely understood, but is imperative for organelle function
and essential for the maintenance of an interconnected organelle network that is finely
tuned to the metabolic needs of the cell. Further elucidation of the mechanisms of
mitochondrial turnover in muscle could offer potential therapeutic targets for the
advancement of health and longevity among our ageing populations. As well, investigating
exercise modalities that are both convenient and capable of inducing robust mitochondrial
adaptations are useful in fostering more widespread global adherence. To this point,
exercise remains the most potent behavioural therapeutic approach for the improvement
of mitochondrial health, not only in muscle, but potentially also in other tissues.
</p>
During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases.
Exercise promotes longevity and ameliorates type 2 diabetes mellitus and insulin resistance. However, exercise also increases mitochondrial formation of presumably harmful reactive oxygen species (ROS). Antioxidants are widely used as supplements but whether they affect the health-promoting effects of exercise is unknown. We evaluated the effects of a combination of vitamin C (1000 mg/day) and vitamin E (400 IU/day) on insulin sensitivity as measured by glucose infusion rates (GIR) during a hyperinsulinemic, euglycemic clamp in previously untrained (n = 19) and pretrained (n = 20) healthy young men. Before and after a 4 week intervention of physical exercise, GIR was determined, and muscle biopsies for gene expression analyses as well as plasma samples were obtained to compare changes over baseline and potential influences of vitamins on exercise effects. Exercise increased parameters of insulin sensitivity (GIR and plasma adiponectin) only in the absence of antioxidants in both previously untrained (P < 0.001) and pretrained (P < 0.001) individuals. This was paralleled by increased expression of ROS-sensitive transcriptional regulators of insulin sensitivity and ROS defense capacity, peroxisome-proliferator-activated receptor gamma (PPARgamma), and PPARgamma coactivators PGC1alpha and PGC1beta only in the absence of antioxidants (P < 0.001 for all). Molecular mediators of endogenous ROS defense (superoxide dismutases 1 and 2; glutathione peroxidase) were also induced by exercise, and this effect too was blocked by antioxidant supplementation. Consistent with the concept of mitohormesis, exercise-induced oxidative stress ameliorates insulin resistance and causes an adaptive response promoting endogenous antioxidant defense capacity. Supplementation with antioxidants may preclude these health-promoting effects of exercise in humans.
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