Optimising Skeletal Muscle Function

Optimising Skeletal Muscle Function

Professor Luis Vitetta and Dr Samantha Coulson
Medlab Clinical Ltd

Optimise Sports Function Physical exercise is vital for maintaining skeletal muscle mass and function throughout a lifetime. Peak muscle mass and strength occurs up until the third decade of life, from which time muscle mass loss naturally occurs, however the extent to which this occurs is determined by numerous factors such as physical activity, diet, genetics and hormonal changes. The term sarcopenia is used to describe this loss of muscle tissue associated with aging that is characteristic with the loss of muscle strength and mobility.1 A number of prudent dietary and lifestyle changes can however assist in slowing muscle mass loss by promoting optimal mitochondrial function, cellular energy metabolism, the regulation and turn-over muscle protein metabolism and assist with glycaemic control.


Leucine

Dietary protein intake is required to provide the twenty (20) naturally occurring amino acids (AAs) and importantly to provide nine (9) indispensable or essential AAs. Amino acids are required for numerous metabolic pathways including neurotransmitter synthesis, production of signalling molecules such as nitrous oxide and essentially are used to synthesize new proteins.2 Leucine is a branched chain amino acid (BCAA) that demonstrates some unique metabolic and protein synthesizing properties compared to other AAs.

While leucine is essential for protein production as with other AAs, it is a unique regulator of muscle protein synthesis particularly after endurance exercise, inducing the sparing of lean body mass. This mechanism involves leucine’s role in stimulating the mTOR kinase activity pathway in the cell. Via the mTOR pathway leucine enhances global rates of protein synthesis. Leucine’s ability to perform such functions is proportional both to its availability and intracellular concentration.2 Further, in vitro studies have demonstrated that leucine modulates fatty acid release from adipocytes and then promotes fatty acid oxidation in skeletal muscle cells, utilising the fatty acids as an energy substrate to support leucine-stimulated protein synthesis. In addition, it has been found that leucine can increase mitochondrial biogenesis/mass in myocytes and adipocytes (in vitro) and also stimulates oxygen consumption that supports the role of leucine in regulating energy metabolism.3


Magnesium Orotate

Mitochondrial organelles are present in most eukaryotic cells and are integral to the respiratory complex and so energy production, but also other vital cellular metabolic pathways such as pyrimidine nucleotide synthesis. A critical compound involved in nucleotide synthesis is Orotate or Orotic acid. Dihydro-orotate dehydrogenase (DHODH) catalyses the de novo synthesis of pyrimidine nucleotides by converting dihydro-orotate to Orotate. This reaction also relies on ubiquinone linking mitochondrial respiratory chain and pyrimidine biosynthesis.4,5 The orotate that is formed is converted into uridine monophosphate (UMP) that is vital to the synthesis and turn-over of DNA / RNA, phospholipids, proteins, glycogen and glycoproteins metabolism (Figure 1). Molecular synthesis of UMP and resulting compounds can be disrupted by certain medications that affect the Mevalonate pathway. Suppression of DHODH affects cell growth and mitochondrial function. Supplementing with Magnesium Orotate can assist to bypass the resultant aberrant mitochondrial dysfunction by providing the precursor to uridine synthesis.

With increasing age, there is natural loss of mitochondria from skeletal muscle and it is well known in leading to a decline in phosphorylation capacity. A 25% loss of muscle mitochondria correlates with a 30% reduction in the capacity of each mitochondrion to generate ATP. This is associated with reduced mitochondrial phosphorylation capacity likely due to altered mitochondrial coupling and its oxido-reductase regulatory system that is very much dependent on Coenzyme Q10. It has been suggested however that in the early stages, mitochondrial dysfunction is not permanent and can be improved with endurance exercise training. Such training is hypothesized to increase mitochondrial turnover and to promote synthesis/repair of mitochondrial membranes.6 Mitochondrial turnover and membrane synthesis is dependent on the mitochondrial UMP pathway. Therefore, in conjunction with endurance exercise, Orotate and Coenzyme Q10 may offer metabolic benefits in assisting with healthy mitochondrial turnover and capacity with ageing and hence muscle strength, function and exercise capability.5

Uridine Nucleotide Synthesis

Figure 1. Uridine nucleotide synthesis



Probiotics

Probiotics It is known that during endurance exercise, particularly in hot humid conditions, that the exercise-induced reduction in intestinal blood flow and thermal damage increases gastrointestinal (GIT) permeability together with an inflammatory response that affects exercise performance. Dehydration is also a major contributing factor. GIT symptoms during exercise include cramping, bloating, diarrhoea and vomiting. Physical damage to the GIT tight junction barrier during exercise may lead to endotoxemia, the translocation of bacteria from the gut lumen into the circulation that triggers a local and subsequent systemic inflammatory response that could potentially cause a further rise in body temperature.7,8 Tight junction proteins maintain a tight paracellular space between enterocytes, regulating the movement of fluid, macromolecules and bacteria between the intestinal lumen and blood stream and their integrity is physiologically regulated by the zonulin molecules and the activity of intestinal-macrophages.9,10

Probiotic bacteria and yeasts are reported to preserve GIT tight junction integrity decreasing permeability and bacterial translocation. This includes Saccharomyces boulardii,11 Lactobacillus gasseri ,12 Lactobacillus plantarum,13 and Bifidobacterium breve.14 Two recent studies have demonstrated that supplementing athletes with a multi species probiotic during exercise reduced GIT permeability and increased run time to fatigue.7,8 Further, sufficient evidence exists to support the role of probiotic bacteria in improving and maintaining GIT tight junction integrity, the recovery of intestinal-macrophage homeostasis that thereby reduces pro-inflammatory cytokine synthesis. Key is the ability of probiotic bacteria to prevent zonulin break-down from the tight junctions of the enterocytes, which ultimately causes intestinal-epithelial degradation.15 In addition, physical activity and environmental heat stress can substantially increase water and electrolyte losses therefore maintaining hydration is an important challenge in preventing fatigue. Even when mild dehydration occurs, endurance exercise performance is negatively affected. Replenishing with sodium, chloride, potassium, citrate and glucose is key to preventing dehydration during physical activity.


Conclusion

Physical activity is vital for maintaining skeletal muscle mass and function but also mitochondrial biogenesis; the dysfunction of which is associated with aging. Certain molecules are known to be involved in skeletal muscle protein synthesis and mitochondrial function that may complement the undertaking of physical activity, both in the young and old. Furthermore, intense exercise is associated with numerous GIT symptoms, increased permeability and inflammatory responses that can be addressed by supplementing with various species of probiotic bacteria. Reducing dehydration is imperative to negate the negative side effects on endurance exercise, and is also beneficial for GIT health.



References

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  4. Fang J, Uchiumi T, Tagi M, et al. Dihydro-orotae dehydrogenase is physically associated with the respiratory complex and its loss leads to mitochondrial dysfunction. Biosci Rep 2013;33:217-227.
  5. Vitetta L, Linnane AW. Personal communication [Patented Intellectual Property]. 2012.
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  11. McFarland LV. Systemic review and meta-analysis of Saccharomyces boulardii W J Gastroenterol J Clin Densitom 2010 16:2202-2222.
  12. Akama F, Nishino R, Makino S, et al. The effect of probiotics on gastric mucosal permeability in humans administered with aspirin. Scand J Gastroenterol 2011;46:831-6.
  13. Ahrne S, Hagslatt ML. Effect of lactobacilli on paracellular permeability in the gut. Nutrients 2011;3:104-17.
  14. Heyman M, Terpend K, Menard S. Effects of specific lactic acid bacteria on intestinal permeability to macromolecules and the inflammatory condition. Acta Paediatr Suppl 2005;94:34-6.
  15. Vitetta L, Briskey D, Hayes E. A review of the pharmacobiotic regulation of gastrointestinal inflammation by probiotics, commensal bacteria and prebiotics. Inflammopharmacol 2012;20:251-266.

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