RNA-seq profiling, and impaired autophagic process in skeletal muscle of MELAS.

Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a common subtype of mitochondrial disease with high disability and mortality rate. The molecular mechanisms of MELAS are largely unknown and whether autophagy is activated in this disease remains controversial. In this work, we reported whole transcriptome profiling of skeletal muscle of MELAS patients and age-matched controls. Analyses revealed that MELAS patients had 224 differentially expressed genes (174 down-regulated, 50 up-regulated) compared to age-matched controls. Most of these genes relevant to MELAS are involved in signal transduction, metabolic process and immune system process. However, the RNA-seq data indicated that autophagy was not altered in MELAS. Functional assays showed that increased reactive oxygen species (ROS), decreased ATP production and decreased lysosome content in fibroblasts derived from MELAS patients, suggesting that mitochondrial dysfunction and degradation deficiency in MELAS. Furthermore, Western-blot analyses using skeletal muscle and fibroblasts derived from MELAS patients showed that autophagy was impaired in MEALS since two important autophagic genes: Beclin-1 and LC3-II, were significantly down-regulated. In conclusion, our study identified molecules and pathways involved in the mechanisms of MELAS, and the impairment of autophagy in this disease, which may serve as the potential therapeutic target for MELAS.