The aryl hydrocarbon receptor: A modulator of skeletal muscle health and aging

Skeletal muscle is fundamental to human health, serving as the primary effector of movement and a central regulator of systemic metabolism. Age-related declines in muscle mass and mitochondrial function contribute to frailty, metabolic dysfunction, and loss of independence in older adults. While these changes are often attributed to reduced physical activity, chronic inflammation, and impaired regenerative capacity, emerging evidence implicates environmental and metabolic sensing pathways in muscle degeneration. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor best known for mediating responses to environmental pollutants such as dioxins, has recently been recognized as a key regulator of endogenous metabolic and redox processes. AHR activation occurs not only through xenobiotic exposure but also via endogenous ligands derived from tryptophan metabolism-including kynurenine and indole derivatives-whose levels rise in aging, chronic kidney disease (CKD), and other pollutant exposures. Sustained AHR activation in skeletal muscle has been shown to impair mitochondrial oxidative phosphorylation, promote proteolysis, and disrupt neuromuscular junction integrity, linking AHR signaling to muscle pathology. Experimental studies in rodent models demonstrate that pharmacologic or genetic inhibition of AHR can preserve muscle mass, mitochondrial function, and regenerative capacity. This review summarizes the molecular biology of the AHR, its emerging roles in skeletal muscle physiology and pathology, and the growing experimental toolkit for interrogating its function. Understanding how AHR signaling integrates environmental, metabolic, and aging cues may reveal new therapeutic opportunities to preserve skeletal muscle health and physical function across the lifespan.