Mitochondrial biogenesis is a target of many aging interventions. While the induction of mitochondrial biogenesis is generally thought to be beneficial, our data indicate that activating mitochondrial biogenesis at old age drives the intracellular accumulation of mitochondrial DNA (mtDNA) deletion mutations and results in an 18% loss of muscle fibers and a 1,200% increase in electron transport chain (ETC) deficient muscle fiber segments. These effects were antagonistically pleiotropic; they were not observed in treated young rats. Based on our data, up-regulation of mitochondrial biogenesis in aged humans may cause significant skeletal muscle damage. These studies will clarify the role of mitochondrial biogenesis in mtDNA deletion mutation accumulation and evaluate the old-age specific effects of compounds that stimulate mitochondrial biogenesis in skeletal muscle. Project outcomes: Specify the cellular pathways and ages at which inducing mitochondrial biogenesis increases mtDNA deletion mutation frequency, ETC deficiencies and fiber loss. Infer the causality of mitochondrial biogenesis in fiber loss by specifying the order of events and time required between mitochondrial biogenesis, mtDNA deletion mutation accumulation and cell death. Determine whether other AMPK or peroxisome proliferator-activated receptor agonists, which target mitochondrial biogenesis, also induce deletion mutation accumulation and cell death when initiated at old ages. Downregulate mitochondrial biogenesis in old rats to prevent ETC deficiencies and fiber loss. By understanding the mechanisms and impacts of inducing mitochondrial biogenesis at old ages, we will specify targets and treatment strategies that mitigate the antagonistic effects.

Public Health Relevance

A significant contributor to aging is the chronic loss of individual cells throughout the lifespan. With age, 46 percent of the muscle cells are lost, leading to frailty, a rapidly growing challenge to aging Americans. These studies will test mechanisms and explore interventions that affect the accumulation of mutations within the mitochondrial genome, muscle cell loss and muscle function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG055518-03
Application #
9716535
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Fridell, Yih-Woei
Project Start
2017-09-30
Project End
2022-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Bielas, Jason; Herbst, Allen; Widjaja, Kevin et al. (2018) Long term rapamycin treatment improves mitochondrial DNA quality in aging mice. Exp Gerontol 106:125-131