Activated mTOR signaling pathway in myofibers with inherited metabolic defect might be an evidence for mTOR inhibition therapies

Background: Abnormally activated mechanistic target of rapamycin (mTOR) pathway has been reported in several model animals with inherited metabolic myopathies (IMMs). However, the profiles of mTOR pathway in skeletal muscles from patients are still unknown. This study aimed to analyze the activity of mTOR pathway in IMMs muscles. Methods: We collected muscle samples from 25 patients with mitochondrial myopathy (MM), lipid storage disease (LSD) or Pompe disease (PD). To evaluate the activity of mTOR pathway in muscle specimens, phosphorylation of S6 ribosomal protein (p-S6) and p70S6 kinase (p-p70S6K) were analyzed by Western blotting and immunohistochemistry. Results: Western blotting results showed that p-p70S6K/p70S6K in muscles from LSD and MM was up-regulated when compared with normal controls (NC) (NC vs. LSD, U= 2.000, P= 0.024; NC vs. MM: U= 6.000, P= 0.043). Likewise, p-S6/S6 was also upregulated in muscles from all three subgroups of IMMs (NC vs. LSD, U= 0.000, P= 0.006; NC vs. PD, U= 0.000, P= 0.006; NC vs. MM, U= 1.000, P = 0.007). Immunohistochemical study revealed that p-S6 was mainly expressed in fibers with metabolic defect. In MM muscles, most p-S6 positive fibers showed cytochrome C oxidase (COX) deficiency (U= 5.000, P= 0.001). In LSD and PD muscles, p-S6 was mainly overexpressed in fibers with intramuscular vacuoles containing lipid droplets (U= 0.000, P = 0.002) or basophilic materials (U= 0.000, P= 0.002). Conclusion: The mTOR pathway might be activated in myofibers with various metabolic defects, which might provide evidence for mTOR inhibition therapy in human IMMs. Key words: mTOR pathway; Mitochondrial myopathy; Lipid storage disease; Pompe disease