Muscle 3243A -> G mutation load and capacity of the mitochondrial energy-generating system
ABSTRACT The mitochondrial energy-generating system (MEGS) encompasses the mitochondrial enzymatic reactions from oxidation of pyruvate to the export of adenosine triphosphate. It is investigated in intact muscle mitochondria by measuring the pyruvate oxidation and adenosine triphosphate production rates, which we refer to as the "MEGS capacity." Currently, little is known about MEGS pathology in patients with mutations in the mitochondrial DNA. Because MEGS capacity is an indicator for the overall mitochondrial function related to energy production, we searched for a correlation between MEGS capacity and 3243A-->G mutation load in muscle of patients with the MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) syndrome.
In muscle tissue of 24 patients with the 3243A-->G mutation, we investigated the MEGS capacity, the respiratory chain enzymatic activities, and the 3243A-->G mutation load. To exclude coinciding mutations, we sequenced all 22 mitochondrial transfer RNA genes in the patients, if possible.
We found highly significant differences between patients and control subjects with respect to the MEGS capacity and complex I, III, and IV activities. MEGS-related measurements correlated considerably better with the mutation load than respiratory chain enzyme activities. We found no additional mutations in the mitochondrial transfer RNA genes of the patients.
The results show that MEGS capacity has a greater sensitivity than respiratory chain enzymatic activities for detection of subtle mitochondrial dysfunction. This is important in the workup of patients with rare or new mitochondrial DNA mutations, and with low mutation loads. In these cases we suggest to determine the MEGS capacity.
SourceAvailable from: Raphael GP Denis[Show abstract] [Hide abstract]
ABSTRACT: Myostatin (Mstn) participates in the regulation of skeletal muscle size and emerges as a reg-ulator of muscle metabolism. We here hypothesized that lack of myostatin profoundly de-presses oxidative phosphorylation dependent muscle function. For this extent, we explored Mstn-/- mice as a model for the constitutive absence of myostatin and AAV-mediated over-expression of myostatin propeptide as a model of myostatin blockade in adult wildtype mice. We show that muscles from Mstn-/- mice, although larger and stronger, fatigue ex-tremely rapidly. Myostatin deficiency shifts muscle from aerobic towards anaerobic energy metabolism as evidenced by decreased mitochondrial respiration, reduced expression of PPAR transcriptional regulators, increased enolase activity, and exercise induced lactic acido-sis. In consequence, constitutively reduced myostatin signaling diminishes exercise capacity, while the hypermuscular state of Mstn-/- mice increases oxygen consumption and the energy cost of running. We wondered whether these results are the mere consequence of the con-genital fiber-type switch towards a glycolytic phenotype of constitutive Mstn-/- mice. Hence we over-expressed myostatin propeptide in adult mice, which did not affect fiber-type dis-tribution, while nonetheless causing increased muscle fatigability, diminished exercise ca-pacity and decreased Pparb/d and Pgc1a expression. In conclusion, our results suggest that myostatin endows skeletal muscle with high oxidative capacity and low fatigability, thus reg-ulating the delicate balance between muscle mass, muscle force, energy metabolism and endurance capacity.AJP Regulatory Integrative and Comparative Physiology 06/2014; 307(4). DOI:10.1152/ajpregu.00377.2013 · 3.53 Impact Factor
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ABSTRACT: Clinical disorders known to affect inherited gamma-amino butyric acid (GABA) metabolism are autosomal reces-sively inherited succinic semialdehyde dehydrogenase and GABA-transaminase deﬁciency. The clinical presentation of succinic semialdehyde dehydrogenase deﬁciency includes intellectual disability, ataxia, obsessive-compulsive disorder and epilepsy with a nonprogressive course in typical cases, although a progressive form in early childhood as well as deterioration in adulthood with worsening epilepsy are reported. GABA-transaminase deﬁciency is associated with a severe neonatal-infantile epileptic encephalopathy.