Abstract
Hereditary myopathy with lactic acidosis (HML) is an autosomal recessive disease caused by an intronic one-base mutation in the iron-sulfur cluster assembly (ISCU) gene, resulting in aberrant splicing. The incorrectly spliced transcripts contain a 100 or 86 bp intron sequence encoding a non-functional ISCU protein, which leads to defects in several Fe-S containing proteins in the respiratory chain and the TCA cycle. The symptoms in HML are restricted to skeletal muscle, and it has been proposed that this effect is due to higher levels of incorrectly spliced ISCU in skeletal muscle compared with other energy-demanding tissues. In this study, we confirm that skeletal muscle contains the highest levels of incorrect ISCU splice variants compared with heart, brain, liver and kidney using a transgenic mouse model expressing human HML mutated ISCU. We also show that incorrect splicing occurs to a significantly higher extent in the slow-twitch soleus muscle compared with the gastrocnemius and quadriceps. The splicing factor serine/arginine-rich splicing factor 3 (SRSF3) was identified as a potential candidate for the slow fiber specific regulation of ISCU splicing since this factor was expressed at higher levels in the soleus compared to the gastrocnemius and quadriceps. We identified an interaction between SRSF3 and the ISCU transcript, and by overexpressing SRSF3 in human myoblasts we observed increased levels of incorrectly spliced ISCU, while knockdown of SRSF3 resulted in decreased levels. We therefore suggest that SRSF3 may participate in the regulation of the incorrect splicing of mutant ISCU and may, at least partially, explain the muscle-specific symptoms of HML.
Highlights
Patients suffering from the autosomal recessive disease hereditary myopathy with lactic acidosis (HML) were first described in 1964 by Larsson et al [1]
We investigated the splicing of mutated iron-sulfur cluster assembly (ISCU) in a range of different tissues using a transgenic mouse model expressing human ISCU carrying the HML mutation
We identified serine/arginine-rich splicing factor 3 (SRSF3) as a splicing factor that may be involved in the muscle-type-specific splicing of ISCU
Summary
Patients suffering from the autosomal recessive disease hereditary myopathy with lactic acidosis (HML) were first described in 1964 by Larsson et al [1]. The patients displayed poor physical performance and a decreased tolerance to exercise, in which even low-level exercise resulted in symptoms such as palpitations, dyspnea, muscle cramps, and tachycardia as well as an increased release of pyruvate and lactate. Muscle-Type-Specific Splicing of ISCU Caused by the HML Mutation induce severe episodes of the disease, characterized by severe acidosis and myoglobinuria, to such an extent that it can be fatal [1, 2]. These observations suggest pathological muscle metabolism in HML patients
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