Substrate kinetics in patients with disorders of skeletal muscle metabolism.

The main purpose of the following studies was to investigate pathophysiological mechanisms in fat and carbohydrate metabolism and effect of nutritional interventions in patients with metabolic myopathies and in patients with severe muscle wasting. Yet there is no cure for patients with skeletal muscle disorders. The group of patients is heterozygous and this thesis is focused on patients with metabolic myopathies and low muscle mass due to severe muscle wasting. Disorders of fatty acid oxidation (FAO) are, along with myophosphorylase deficiency (McArdle disease), the most common inborn errors of metabolism leading to recurrent episodes of rhabdomyolysis in adults. Prolonged exercise, fasting, and fever are the main triggering factors for rhabdomyolysis in these conditions, and can be complicated by acute renal failure. Patients with low muscle mass are in risk of loosing their functional skills and depend on a wheel chair and respiratory support. We used nutritional interventions and metabolic studies with stable isotope technique and indirect calorimetry in patients with metabolic myopathies and patients with low muscle mass to get information of the metabolism of the investigated diseases, and to gain knowledge of the biochemical pathways of intermediary metabolism in human skeletal muscle. We have shown that patients with fat metabolism disorders in skeletal muscle affecting the transporting enzyme of fat into the mitochondria (carnitine palmitoyltransferase II deficiency) and affecting the enzyme responsible for breakdown of the long-chain fatty acids (very long chain acyl-CoA dehydrogenase deficiency) have a normal fatty acid oxidation at rest, but enzyme activity is too low to increase fatty acid oxidation during exercise. Furthermore, these patients benefit from a carbohydrate rich diet. Oppositely is exercise capacity worsened by a fat-rich diet in these patients. The patients also benefit from IV glucose, however, when glucose is given orally just before exercise, exercise capacity is worsened, most likely due to the sympatho-adrenergt response, that increases heart rate and blocks gluconeogenesis. Substrate turnover studies in patients with McArdle disease and phosphorylase b kinase deficiency showed that palmitate lipolysis, utilization and plasma concentration was higher and total CHO lower in the patients during exercise vs. healthy subjects. In patients with low muscle mass glucose homeostasis is impaired, and our findings showed that these patients are prone to develop hypoglycaemia during prolonged fasting. The following studies emphasize the importance of skeletal muscle in production of energy, both when skeletal muscle lack important metabolic enzymes (metabolic myopathies), and when skeletal muscle mass is low.