Sarcopenia is the loss of muscle mass and muscle strength that occurs in aging people. The resulting loss of muscle strength contributes to impairments in physical functioning in older people and serves as a risk factor for loss of independence, need for nursing home placement, and ultimately mortality. Currently there are no treatments for sarcopenia and the cause(s) are incompletely understood. Hence there is a need to identify new ways to study sarcopenia and identify mechanisms that may be amenable to intervention. During aging, C. elegans develops sarcopenia, and mutations in the insulin/IGF-1 receptor daf-2 delay the development of sarcopenia. We have found that mvk-1, which is the worm homolog of the mevalonate kinase gene, is required for this delay. Mevalonate kinase is involved in the conversion of mevalonate to isoprenoids, ubiquinone, and cholesterol, and this enzyme lies in a metabolic pathway targeted by the commonly used statin medications. Statins have well-known toxic effects on muscle, but the cause of these adverse effects is still under active study. Among ubiquinone, isoprenoids, and cholesterol, we have found ubiquinone to be the required output of the mevalonate pathway with regards to muscle aging. Ubiquinone is the electron acceptor for complex I and complex II of the mitochondrial electron transport chain. Prior work has shown that daf-2 mutants have elevated complex I and II activity, and mitochondrial activity is better preserved in the daf-2 mutants during aging compared to wild-type animals. Additionally, complex I activity in muscle and other tissues declines during aging in vertebrates. These findings led us to hypothesize that mitochondrial activity is a driver of the development of sarcopenia during aging and perhaps is involved in statin toxicity. To test this hypothesis we propose to (1) examine muscle structure during aging in wild-type worms, daf-2 mutants, and daf-2 mutants with reduced ubiquinone levels;(2) test whether aging and low ubiquinone levels impair mitochondrial ATP production or (3) lead to increased ROS production during aging;(4) determine the consequences of directly manipulating complex I activity both up and down on muscle function;and (5) conduct a pilot compound screen using drugs used for genetic mitochondrial illnesses to test for improvements in muscle function during aging. A novel aspect of our work will be the use of recently developed fluorescent proteins to longitudinally and non-invasively measure cellular ATP levels and ROS production in the muscles of aging animals. Together our project can provide insights into the roles of mitochondrial dysfunction in muscle during aging or in response to impaired ubiquinone synthesis due to medications such as statins.

Public Health Relevance

Our project studies how aging and ubiquinone production influence muscle structure and function as well as mitochondrial function. We believe that both aging and the use of statin medications can impair mitochondrial function and lead to similar types of adverse changes in muscle. From this research, we hope to gain insights that can lead to new treatments to preserve or improve muscle function in older people and to perhaps make the use of statin medications safer.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG044768-01A1
Application #
8367877
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Williams, John
Project Start
2012-08-01
Project End
2013-06-30
Budget Start
2012-08-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$312,625
Indirect Cost
$107,625
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Cai, Liquan; Wang, Dan; Fisher, Alfred L et al. (2014) Identification of a genetic interaction between the tumor suppressor EAF2 and the retinoblastoma protein (Rb) signaling pathway in C. elegans and prostate cancer cells. Biochem Biophys Res Commun 447:292-8
Wang, Hongning; Karadge, Uma; Humphries 4th, William H et al. (2014) Analyzing cell physiology in C. elegans with fluorescent ratiometric reporters. Methods 68:508-17