Buck Institute for Research on Aging

Metabolic Basis of Environmental Stress Signaling in Skeletal Muscle

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A hallmark of aging is the decrease in regenerative capacity of tissues. It is being recognized that the decrease in regenerative capacity is related to a decreased capacity of stem cells to renew themselves and to differentiate into their defined lineages. An important factor in affecting health and the ability of the body to repair itself is environmental stress like xenobiotic chemicals. The source of these molecules can be from dietary natural compounds, or from synthetic/smoke-associated chemicals.

A relatively unexplored factor in aging is the role of xenobiotic stress. Tissues, including skeletal muscle are chronically exposed to xenobiotic stress throughout the lifetime of an organism. How the xenobiotic stress response pathway affects skeletal muscle stem cells is unknown.

The aryl hydrocarbon receptor (Ahr) is a ligand activated ‘master transcription factor’ that regulates the response to xenobiotic stress in mammalian cells. We seek to understand the physiological basis of this stress signaling pathway, to discover mechanisms by which AhR might alter stem cell metabolism. Ahr was originally discovered as the receptor for the environmental toxin 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD).

In this proposal we use mass-spectrometry based approaches to understand how environmental chemicals, signal via AhR, to modulate the physiology of muscle cells. The rationale for the project is that, once it is known how Ahr and its ligands modulate cellular physiology; this pathway can be effectively targeted for therapies against aging and age-related stem cell dysfunction.