Facilitated By

San Antonio Medical Foundation

The Effects of Chronic Mtor Inhibition on Aging Muscle and Mitochondrial Function

UT Health San Antonio

The UT Health San Antonio, with missions of teaching, research and healing, is one of the country’s leading health sciences universities.

Principal Investigator(s)
Webster, Phillip Justin
Funded by
NIH
Research Start Date
Status
Active

The Effects of Chronic mTOR Inhibition on Aging Muscle and Mitochondrial Function Sarcopenia is the age-dependent loss of skeletal muscle mass and function that begins early in adulthood and progresses into old age. These losses can increase the incidence of falls, morbidity, and severely impair the well-being of older people. The current therapies are insufficient to reverse these losses, so identifying key pathways could open up new therapeutic options which is particularly pressing given the rapid increase in the population of older people with the aging of the Baby Boom generation. Mitochondrial dysfunction is commonly observed in sarcopenia, though whether mitochondrial dysfunction plays a causal role in the process or whether improved mitochondrial function is sufficient to attenuate sarcopenia is unknown. We and others have found that inhibition of the target of rapamycin kinase (TOR) increases muscle function in the non-parasitic nematode C. elegans during aging. Further, I have utilized novel transgenic animals expressing fluorescent reporters of mitochondrial activity to demonstrate that TOR inhibition also preserves mitochondrial function during aging. The effects of TOR inhibition on lifespan involve the activation of several downstream pathways, such as the activation of the HLH-30/TFEB transcription factor which promotes autophagy and the inhibition of protein translation. Both of these pathways share a link with a specialized form of autophagy, termed mitophagy, which involves the autophagic degradation of mitochondria. In particular, the mitophagy process is promoted via the DCT-1 protein which binds to the surface of mitochondria. Hence, TOR inhibition may not only activate macroautophagy, but also mitophagy to promote improved mitochondrial function during aging. We hypothesize that chronic TOR inhibition engages HLH-30 to directly activate DCT-1, which then promotes mitophagy to preserve mitochondrial activity and muscle function during aging. To test this hypothesis I propose to (1) determine if TOR regulates dct-1 expression via activation of the HLH-30/TFEB transcription factor using RNAi, a dct-1:gfp reporter, and qPCR; (2) determine if preserved mitochondrial function is mediated by mitophagy using in vivo fluorescent reporters for mitochondrial ATP, NADH, and H2O2 production.; and (3) determine if enhanced mobility is dependent on mitophagy using RNAi and a novel electrotaxis-based mobility assay. A novel aspect of my work is to use in vivo fluorescent proteins to detect changes in mitochondrial function. Furthermore, I will utilize a novel electrotaxis-based mobility assay to measure age-associated changes in muscle function. Finally, this study will describe a mitophagy mechanism, independent of macroautophagy mechanisms, within the context of TOR activity and longevity. This will not only address a prevailing question in aging, but also lead to better understanding of mitochondrial dynamics, which is essential for understanding degenerative diseases. In addition to the research plan, this proposal describes a training plan focused on gaining expertise in the C. elegans model, gaining knowledge in the Biology of Aging, and promoting career development towards obtaining a post-doctoral position and my ultimate goal of becoming an independent investigator in the Aging field. PUBLIC HEALTH RELEVANCE: Sarcopenia is the age related decline in skeletal muscle mass and function that adversely affects the health of approximately 50% of men and 74% of women over the age of 65. Muscle wasting is associated with functional impairment, development of physical disability, and increases in fall related injuries. As our aging population grows, our research in signaling pathways that contribute to muscle wasting can lead to the development of novel treatments and therapies in older people.

Disease Modeling
Aging
Neuroscience