It has been reported that feeding mice resveratrol activates AMPK and SIRT1 in skeletal muscle leading to deacetylation and activation of PGC-1α, increased mitochondrial biogenesis, and improved running endurance. This study was done to further evaluate the effects of resveratrol, SIRT1, and PGC-1α deacetylation on mitochondrial biogenesis in muscle. Feeding rats or mice a diet containing 4 g resveratrol/kg diet had no effect on mitochondrial protein levels in muscle. High concentrations of resveratrol lowered ATP concentration and activated AMPK in C₂C₁₂ myotubes, resulting in an increase in mitochondrial proteins. Knockdown of SIRT1, or suppression of SIRT1 activity with a dominant-negative (DN) SIRT1 construct, increased PGC-1α acetylation, PGC-1α coactivator activity, and mitochondrial proteins in C₂C₁₂ cells. Expression of a DN SIRT1 in rat triceps muscle also induced an increase in mitochondrial proteins. Overexpression of SIRT1 decreased PGC-1α acetylation, PGC-1α coactivator activity, and mitochondrial proteins in C₂C₁₂ myotubes. Overexpression of SIRT1 also resulted in a decrease in mitochondrial proteins in rat triceps muscle. We conclude that, contrary to some previous reports, the mechanism by which SIRT1 regulates mitochondrial biogenesis is by inhibiting PGC-1α coactivator activity, resulting in a decrease in mitochondria. We also conclude that feeding rodents resveratrol has no effect on mitochondrial biogenesis in muscle. Studies on cultured muscle cells have shown that treatment with resveratrol, a chemical famously found in the skin of red grapes, stimulates the manufacture of new mitochondria. This has been attributed to the activation of the deacetylase SIRT1 either directly by resveratrol or indirectly via the activation of AMP-activated protein kinase (AMPK). SIRT1 is then thought to deacetylate and activate the transcriptional coactivator PGC-1α, which in turn stimulates mitochondrial biogenesis. It has also been reported that feeding resveratrol to mice increases muscle mitochondria and results in improved running endurance. Here we further analyze the adaptive response of muscle mitochondria to resveratrol treatment to see if it mimics the response to endurance exercise. We find that feeding rats or mice large amounts of resveratrol did not increase muscle mitochondria. In these rodents, the bioavailability of oral resveratrol is low, and the resulting plasma level of resveratrol is far below the concentration required to activate AMPK. Contrary to previous reports we find that deacetylation by SIRT1 decreases PGC-1α activity and results in a decrease in mitochondria; moreover we show that the increase in mitochondria induced in cultured muscle cells by a high resveratrol concentration is due to the toxic activation of AMPK and, in turn, PGC-1α. However, this effect requires resveratrol concentrations that are very much higher than those attained by oral administration, and we conclude that oral resveratrol has no effect on mitochondrial biogenesis in skeletal muscle.

It has been reported that supplementation with the antioxidant vitamins C and E prevents the adaptive increases in mitochondrial biogenesis and GLUT4 expression induced by endurance exercise. We reevaluated the effects of these antioxidants on the adaptive responses of rat skeletal muscle to swimming in a short-term study consisting of 9 days of vitamins C and E with exercise during the last 3 days and a longer-term study consisting of 8 wk of antioxidant vitamins with exercise during the last 3 wk. The rats in the antioxidant groups were given 750 mg·kg body wt⁻¹·day⁻¹vitamin C and 150 mg·kg body wt⁻¹·day⁻¹vitamin E. In rats euthanized immediately after exercise, plasma TBARs were elevated in the control rats but not in the antioxidant-supplemented rats, providing evidence for an antioxidant effect. In rats euthanized 18 h after exercise there were large increases in insulin responsiveness of glucose transport in epitrochlearis muscles mediated by an approximately twofold increase in GLUT4 expression in both the short- and long-term treatment groups. The protein levels of a number of mitochondrial marker enzymes were also increased about twofold. Superoxide dismutases (SOD) 1 and 2 were increased about twofold in triceps muscle after 3 days of exercise, but only SOD2 was increased after 3 wk of exercise. There were no differences in the magnitudes of any of these adaptive responses between the control and antioxidant groups. These results show that very large doses of antioxidant vitamins do not prevent the exercise-induced adaptive responses of muscle mitochondria, GLUT4, and insulin action to exercise and have no effect on the level of these proteins in sedentary rats.

It has been reported that 30% calorie restriction (CR) for 3 mo results in large increases in mitochondrial biogenesis in heart, brain, liver, and adipose tissue, with concomitant increases in respiration and ATP synthesis. We found these results surprising, and performed this study to determine whether 30% CR does induce an increase in mitochondria in heart, brain, liver, adipose tissue, and/or skeletal muscle. To this end, we measured the levels of a range of mitochondrial proteins, and mRNAs. With the exception of long‐chain acyl‐CoA dehydrogenase protein level, which was increased ~60% in adipose tissue, none of the mitochondrial proteins or mRNAs that we measured were increased in rats subjected to 30% CR for 14 wk. There was also no increase in citrate synthase activity. Because it is not possible to have an increase in mitochondria without any increase in key mitochondrial proteins, we conclude that 30% CR does not induce an increase in mitochondria in heart, brain, liver, adipose tissue, or skeletal muscle in laboratory rodents.—Hancock, C. R., Han, D.‐H., Higashida, K., Kim, S. H., Holloszy, J. O. Does calorie restriction induce mito‐chondrial biogenesis? A reevaluation. FASEB J. 25, 785–791 (2011). www.fasebj.org

It has been proposed that muscle insulin resistance in type 2 diabetes is due to a selective decrease in the components of the mitochondrial electron transport chain and results from accumulation of toxic products of incomplete fat oxidation. The purpose of the present study was to test this hypothesis. Rats were made severely iron deficient, by means of an iron-deficient diet. Iron deficiency results in decreases of the iron containing mitochondrial respiratory chain proteins without affecting the enzymes of the fatty acid oxidation pathway. Insulin resistance was induced by feeding iron-deficient and control rats a high fat diet. Skeletal muscle insulin resistance was evaluated by measuring glucose transport activity in soleus muscle strips. Mitochondrial proteins were measured by Western blot. Iron deficiency resulted in a decrease in expression of iron containing proteins of the mitochondrial respiratory chain in muscle. Citrate synthase, a non-iron containing citrate cycle enzyme, and long chain acyl-CoA dehydrogenase (LCAD), used as a marker for the fatty acid oxidation pathway, were unaffected by the iron deficiency. Oleate oxidation by muscle homogenates was increased by high fat feeding and decreased by iron deficiency despite high fat feeding. The high fat diet caused severe insulin resistance of muscle glucose transport. Iron deficiency completely protected against the high fat diet-induced muscle insulin resistance. The results of the study argue against the hypothesis that a deficiency of the electron transport chain (ETC), and imbalance between the ETC and β-oxidation pathways, causes muscle insulin resistance.

An increase in bone mineral density during adolescence increases resistance to fractures in older age. The Korean Society for Bone and Mineral Research and the Korean Society of Exercise Physiology developed exercise guidelines to increase the peak bone mass (PBM) in adolescents based on evidence through a systematic review of previous research. Articles were selected using the systematic method, and the exercise guidelines were established by selecting key questions (KQs) and defining the effects of exercises based on evidence through a literature review for selecting the final exercise method. There were 9 KQs. An online search was conducted on articles published since 2000, and 93 articles were identified. An increase in PBM in adolescence was effective for preventing osteoporosis and fractures in older age. Exercise programs as part of vigorous physical activity (VPA) including resistance and impact exercise at least 5 to 6 months were effective for improving PBM in adolescents. It is recommended that resistance exercise is performed 10 to 12 rep·set-1 1-2 set·region-1 and 3 days·week-1 using the large muscles. For impact exercises such as jumping, it is recommended that the exercise is performed at least 50 jumps·min-1, 10 min·day-1 and 2 days·week-1. Exercise guidelines were successfully developed, and they recommend at least 5 to 6 months of VPA, which includes both resistance and impact exercises. With the development of exercise guidelines, the incidence of osteoporosis and fractures in the aging society can be reduced in the future, thus contributing to improved public health.

Kim JC, et al. Korean J Physiol Pharmacol. 2018 Jul;22(4):427-436. https://doi.org/10.4196/kjpp.2018.22.4.427