Hereditary Abnormal Muscle Metabolism With Hyperkinetic Circulation During Exercise

Abstract

Abstract. Patients with a hereditary myopathy with paroxysmal myoglobinuria were studied in the chronic state of the disease. They were characterized by muscle contractions of fairly normal strength and quite good endurance in exercise with small muscle groups, but a poor physical performance in exercise of some duration with large muscle groups. Several facts indicate that it was not muscular weakness, but the circulatory capacity that was a main factor limiting the physical working capacity in exercise of some duration with large muscle groups. The oxygen uptake was largely normal in relation to the work performed. However, even light exercise on a bicycle ergometer caused tachycardia (approaching maximum heart rate), a high cardiac output (approaching, for the size of the individual, maximum values in the normal range) and an abundant blood flow through the exercising legs. Thus, there were no signs of insufficient heart function, but the utilization of the oxygen of the blood in the exercising limbs was low. The concentration of lactate, and particularly of pyruvate, in the blood, and the lactate and pyruvate production increased more than in the controls for the slight work performed. During exercise the lactate/pyruvate ratio decreased and the calculated “excess of lactate” was negative, while it increased in normal subjects. After exercise the excess lactate was higher in the patients than in the controls. This indicates an abnormal muscle metabolism, probably a decreased capacity for pyruvate oxidation. It is suggested that a metabolic disturbance caused an abnormally large production of metabolites in the working muscles, resulting in muscular vessel dilatation by a local humoral effect. The muscles acted almost like a‐v shunts and, as a consequence, the patients had a hyperkinetic circulation, i.e. a low O2 uptake in relation to cardiac output, a low a‐v O2 difference for mixed venous blood and for the venous blood of the exercising limbs.

Iron –sulfur cluster biogenesis in mammalian cells: New insights into the molecular mechanisms of cluster delivery

“…Hereditary myopathy with lactic acidosis (HML), also known as Swedish myopathy with exercise intolerance [222, 223], was first described in the 1960’s and is an autosomal recessive muscular disorder characterized by childhood onset of exercise intolerance with cramping, dyspnea, palpitations and muscle weakness. Biochemical features of the disease include lactic acidosis and, rarely, rhabdomyolysis and myoglobinuria [222, 224, 225], with impaired muscle oxidative phosphorylation, deficient succinate dehydrogenase [224, 226] and aconitase [227, 228] activities, and the presence of iron aggregates in mitochondria [227, 228].…”

Tissue-specific splicing of ISCU results in a skeletal muscle phenotype in myopathy with lactic acidosis, while complete loss of ISCU results in early embryonic death in mice

“…The patients suffered from low exercise tolerance associated with muscle cramps, tachycardia and shortness of breath, and increased release of lactate and pyruvate even when subjected to a low work load. In severe episodes of the disease, patients experienced widespread fatigue, myoglobinuria and severe acidosis (Larsson et al 1964;Linderholm et al 1969). Biochemical analysis showed defects in complexes I, II and III of the respiratory chain and low levels of mitochondrial aconitase, all of which contain iron-sulphur (Fe-S) centres (Linderholm et al 1990;Hall et al 1993;Haller et al 1991).…”

Tissue Specificity of a Human Mitochondrial Disease

“…The disease is characterized by life-long exercise intolerance in which trivial bouts of exercise can cause tachycardia and palpitations, dyspnea, muscle fatigue, and lactic acidosis (1)(2)(3). Many ISCU myopathy patients experience periods of muscle weakness, pain, and swelling associated with rhabdomyolysis and myoglobinuria followed by muscle regeneration and resolution of these symptoms (1,4).…”