This revised proposal builds on our exciting preliminary findings demonstrafing the power of a mitochondrially targeted anfioxidant to protect skeletal muscle from zidovudine (AZT)-induced dysfuncfion. Due to the success of HIV treatments, which often includes AZT, over 35% of all HIV pafients 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 interacfions between these life-saving therapies and aging on mitochondria remain pooriy understood. AZT and other nucleoside reverse transcriptase inhibitors (NRTl) have significant mitochondrial toxicity that shares many characteristics with aging muscle, including increased mitochondrial mutafions, reduced mitochondrial content, impaired energy producfion, and increased oxidative stress leading to muscle loss and frailty. Despite these similarifies, there have been no studies examining the potential synergisfic effects of aging and NRTl treatment on mitochondrial function in skeletal muscle. In this proposal, we use a common NRTl combinafion, AZT/3TC (combivir), to test whether aging exacerbates NRTI-induced mitochondrial toxicity and whether mitochondrially targeted antioxidants can prevent this mitochondrial dysfuncfion.
Aim 1 (Funcfion) uses state of the art spectroscopic and tradifional approaches to test whether aging worsens the functional decline in AZT/3TC treated muscle and whether mitochondrially targeted catalase (mCAT) is able to prevent this decline.
Aim 2 (Mechanism) elucidates the cellular mechanisms underlying AZT/3TC toxicity and mCAT protecfion 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 mitochondrially targeted anfioxidant pepfides (SS pepfides) 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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG001751-31
Application #
8643176
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
31
Fiscal Year
2014
Total Cost
$303,827
Indirect Cost
$107,176
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Shen, Jiang-Cheng; Fox, Edward J; Ahn, Eun Hyun et al. (2014) A rapid assay for measuring nucleotide excision repair by oligonucleotide retrieval. Sci Rep 4:4894
Kamath-Loeb, Ashwini S; Balakrishna, Sharath; Whittington, Dale et al. (2014) Sphingosine, a modulator of human translesion DNA polymerase activity. J Biol Chem 289:21663-72
Wang, Ying; Wang, Gary Z; Rabinovitch, Peter S et al. (2014) Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-*B-mediated inflammation in macrophages. Circ Res 114:421-33
Szeto, H H; Birk, A V (2014) Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin Pharmacol Ther 96:672-83
Dai, Dao-Fu; Karunadharma, Pabalu P; Chiao, Ying A et al. (2014) Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell 13:529-39
Goh, Jorming; Endicott, Emma; Ladiges, Warren C (2014) Pre-tumor exercise decreases breast cancer in old mice in a distance-dependent manner. Am J Cancer Res 4:378-84
Marcinek, D J; Conley, K E (2014) In vivo metabolic spectroscopy identifies deficits in mitochondrial quality and capacity in aging skeletal muscle. Clin Pharmacol Ther 96:669-71
Dai, Dao-Fu; Chiao, Ying Ann; Marcinek, David J et al. (2014) Mitochondrial oxidative stress in aging and healthspan. Longev Healthspan 3:6
Bartell, Shoshana M; Kim, Ha-Neui; Ambrogini, Elena et al. (2014) FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation. Nat Commun 5:3773
Herr, Alan J; Kennedy, Scott R; Knowels, Gary M et al. (2014) DNA replication error-induced extinction of diploid yeast. Genetics 196:677-91

Showing the most recent 10 out of 255 publications