This revised proposal builds on our exciting preliminary findings demonstrating the power of a mitochondrial targeted antioxidant to protect skeletal muscle from zidovudine (AZT)-induced dysfunction. Due to the success of HIV treatments, which often includes AZT, over 35% of all HIV patients in the US are 50 years and older. New data demonstrates that AZT-induced changes are very different in young and old skeletal muscle. However, the interactions between these life-saving therapies and aging on mitochondria remain poorly understood. AZT and other nucleoside reverse transcriptase inhibitors (NRTl) have significant mitochondrial toxicity that shares many characteristics with aging muscle, including increased mitochondrial mutations, reduced mitochondrial content, impaired energy production, and increased oxidative stress leading to muscle loss and frailty. Despite these similarities, there have been no studies examining the potential synergistic effects of aging and NRTl treatment on mitochondrial function in skeletal muscle. In this proposal, we use a common NRTl combination, AZT/3TC (combivir), to test whether aging exacerbates NRTI-induced mitochondrial toxicity and whether mitochondrial targeted antioxidants can prevent this mitochondrial dysfunction.
Aim 1 (Function) uses state of the art spectroscopic and traditional approaches to test whether aging worsens the functional decline in AZT/3TC treated muscle and whether mitochondrial targeted catalase (mCAT) is able to prevent this decline.
Aim 2 (Mechanism) elucidates the cellular mechanisms underlying AZT/3TC toxicity and mCAT protection in young and old mouse muscle. We combine methods developed during the last P01 grant cycle for measuring changes in the mitochondrial proteome, damage, and quality control processes.
Aim 3 (Translation) tests the potential for translating the protective effects of the transgenic mCAT model to human application. We test whether newly developed mitochondrial targeted antioxidant peptides (SS peptides) can protect against AZT/3TC toxicity in young and old mouse muscles. We combine methods from Aims 1 and 2 to measure in vivo functional outcomes and underlying mechanisms of protection of the SS peptides.
This study has great translational potential for developing new interventions to reduce pathology in conditions where ROS production and mitochondrial dysfunction lead to frailty, such as aging, HIV, cancer and neurodegeneration. The close collaboration with Projects 1, 2 and 3 presents a unique opportunity to determine how mitochondrial targeted antioxidants can be optimized for best effects in multiple disease and organ systems.
|Campbell, Matthew D; Marcinek, David J (2016) Evaluation of in vivo mitochondrial bioenergetics in skeletal muscle using NMR and optical methods. Biochim Biophys Acta 1862:716-24|
|Loeb, Lawrence A (2016) Human Cancers Express a Mutator Phenotype: Hypothesis, Origin, and Consequences. Cancer Res 76:2057-9|
|Treuting, P M; Snyder, J M; Ikeno, Y et al. (2016) The Vital Role of Pathology in Improving Reproducibility and Translational Relevance of Aging Studies in Rodents. Vet Pathol 53:244-9|
|Liu, Sophia Z; Marcinek, David J (2016) Skeletal muscle bioenergetics in aging and heart failure. Heart Fail Rev :|
|Ahn, Eun Hyun; Lee, Seung Hyuk; Kim, Joon Yup et al. (2016) Decreased Mitochondrial Mutagenesis during Transformation of Human Breast Stem Cells into Tumorigenic Cells. Cancer Res 76:4569-78|
|Kruse, Shane E; Karunadharma, Pabalu P; Basisty, Nathan et al. (2016) Age modifies respiratory complex I and protein homeostasis in a muscle type-specific manner. Aging Cell 15:89-99|
|Chiao, Ying Ann; Kolwicz, Stephen C; Basisty, Nathan et al. (2016) Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. Aging (Albany NY) 8:314-27|
|Ahn, Eun Hyun; Hirohata, Kensen; Kohrn, Brendan F et al. (2015) Detection of Ultra-Rare Mitochondrial Mutations in Breast Stem Cells by Duplex Sequencing. PLoS One 10:e0136216|
|Birk, Alexander V; Chao, Wesley M; Liu, Shaoyi et al. (2015) Disruption of cytochrome c heme coordination is responsible for mitochondrial injury during ischemia. Biochim Biophys Acta 1847:1075-84|
|Quarles, Ellen K; Dai, Dao-Fu; Tocchi, Autumn et al. (2015) Quality control systems in cardiac aging. Ageing Res Rev 23:101-15|
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