Browsing by Author "Newell, Christopher"

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    Advancing the Art of Mitochondrial Diagnostics and Therapeutics
    (2017) Newell, Christopher; Khan, Aneal; Shearer, Jane; Rho, Jong; Childs, Sarah; Shutt, Timothy; Haqq, Andrea
    Objective: Mitochondrial diseases are panethnic genetic disorders, affecting 1:5000 individuals. Currently with no cure, challenges exist in patient diagnosis, measurement of mitochondrial function, and effective therapies. The primary emphasis of this dissertation was to explore diagnostic and therapeutic targets for mitochondrial disease. Investigated therapies included; mesenchymal stem cell (MSC) therapy, dietary interventions, and side alternating vibration training (SAVT). Novel diagnostic approaches employed were; the hybrid blue-clear native polyacrylamide gel electrophoresis (BCN-PAGE), and circulating cell-free mitochondrial DNA (cf-mtDNA) techniques. Methods: C57BL/6 mice were intravenously treated with MSCs following the induction of metabolic inflammation through prolonged high-fat (HF) feeding. A separate cohort of BTBR, autism-phenotype, mice were treated with a ketogenic diet (KD) to examine the impact on mitochondrial dynamics in a disease commonly experiencing mitochondrial dysfunction. These projects involved a combination of mitochondrial bioenergetics (high resolution respirometry), gut microbiome (fecal and cecal), gene expression (qRT-PCR, gene microarray), and mitochondrial morphology (confocal microscopy) experimentation to evaluate the mitochondrial-specific response to each therapy. Thirdly, clinical assessment of SAVT as a therapeutic in mitochondrial disease patients was performed using a 12-week cross-over study design using peak jumping power (PJP) as a primary functional measurement of mitochondrial function. Diagnostically, mitochondria were isolated from control and mitochondrial disease patient skin fibroblasts to compare our BCN-PAGE technique to existing diagnoses. Secondly, blood was drawn from both control and mitochondrial disease patients for clinical comparisons of mtDNA hapolotyping using our cf-mtDNA technique. Results: Therapeutic studies indicate that MSCs improve metabolic capacity, induce widespread gene shifting, and promote healthy mitochondrial morphology in a model of metabolic inflammation. Moreover, KD administration exerts tissue-specific effects including increased mitochondrial turnover in liver, while the brain remained tightly regulated. Clinically, SAVT was well tolerated in mitochondrial disease patients, with improvements in PJP being measured following therapy. Diagnostically, both BCN-PAGE and cf-mtDNA techniques were successfully able to corroborate clinical diagnostic findings. Conclusions: Experiments completed in this dissertation provide insight into various therapeutic opportunities for both mitochondrial disease and diseases involving mitochondrial dysfunction. Furthermore, our less-invasive diagnostic techniques may be useful to monitor the response to future therapies for mitochondrial disease.
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    Side alternating vibration training in patients with mitochondrial disease: a pilot study
    (2017-08-08) Newell, Christopher; Ramage, Barbara; Robu, Ion; Shearer, Jane; Khan, Aneal
    Abstract Background Side alternating vibration training (SAVT) is a mechanical oscillation using a vibrating platform that simulates exercise. We hypothesized that patients with mitochondrial myopathies, who experience muscle weakness, may see an improvement in muscle power with SAVT. Methods Patients with mitochondrial disease started either a treatment (SAVT) or control phase (standing without vibration) for 12 weeks, then 12 weeks of washout, and then a 12-week cross-over. The main outcome measure was peak jump power (PJP). We compared this to a natural history cohort from clinic. Results Seven out of 13 patients completed at least 80% of their SAVT sessions and were analyzed. The ΔPJP after the control phase was −2.7 ± 1.7 W/kg (mean ± SEM), SAVT was +2.8 ± 0.6 W/kg (p < 0.05) and from the natural history cohort was −2.4 ± 0.8 W/kg/year. Conclusions SAVT is well tolerated and may improve muscle power in mitochondrial disease patients.