Metabolic myopathies comprise a clinically and etiologically diverse group of disorders caused by defects in mitochondrial energy metabolism. The diagnosis of metabolic myopathies depends on muscle biopsy. The pathological features of muscle biopsy include "ragged red fibers", increased of succinate dehydrogenase activity, decreased of cytochrome c oxidase activity and glycogen or neutral fat accumulation. Recently, the high-throughput assays using the XF Seahorse extracellular flux analyser have been used to examine the mitochondrial functions in patients’ muscle biopsies. Although the molecular mechanisms driving metabolic myopathies are better understood in the last decade, only a few mitochondrial nutrients are in clinical used for therapy today. Because mitochondrial myopathies are rare diseases, there is little incentive to develop new drugs for metabolic myopathies, and it’s also difficult to collect sufficiently number of patients to conduct adequately statistically valid, randomized, double-blinded, placebo-controlled clinical trials. This proposal aimed to isolate human myoblasts from metabolic disorders and immortalized these cells for further investigations. We will explore whether electrical stimulation or mitochondrial nutrients will regulate mitochondrial biogenesis and mitochondrial dynamics that mitochondrial biogenesis and function. Increased mitochondrial number and function may accompany with muscle type switch that increase the oxidative, slow twitch, high endurance muscle fibers that contributes to merits for patients with metabolic myopathies. Our specific aims are:Specific aim (I): To establish myofibroblast cell lines with metabolic myopathies that can be used for further ex-vivo investigations. Primary cultured myofibroblasts will be immortalized in Food Industry Research and Development Institute, so these cells can be used for further analyzed for molecular mechanisms and to explore possible therapeutic agents for metabolic myopathies. These cells can also be used for further drug developments. Specific Aim (II): To test whether electrical stimulation will enhance the mitochondrial biogenesis and modulate mitochondrial dynamic that increases mitochondrial number and function. We have set up an electrical stimulation system using C2C12 myotube. We will examine whether electrical stimulation system may correct the mitochondrial dysfunction in the myotubes prepared from patients with mitochondrial myopathies. Specific Aim (III): To investigate whether supplementation with mitochondrial nutrients will enhance mitochondrial biogenesis and function. We will first examine the bioenergetics profiles of patients with metabolic myopathies using the XF Seahorse extracellular flux analyzer. These results will then be compared with cells treated with different mitochondrial nutrients. These ex-vivo data will provide information for future therapeutic approaches.
|Effective start/end date||8/1/18 → 7/1/19|
- mitochondrial function
- metabolic myopathy
- rare diseases
- XF Seahorse
- mitochondrial dynamic
- mitochondrial nutrients
- α-lipoic acid
- Ubiquinone (CoQ10)
- pyrroloquinoline quinone (PQQ)
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