Muscarinic agonism restores degenerated salivary glands through a calcium-ATP metabolic axis

Chronic damage to tissues and organs is deemed irreversible. This has led to a focus on the development of regenerative therapies that replace tissues. Here, we break with this dogma by demonstrating that the chronically injured degenerating salivary gland can be functionally and structurally restored through a nerve-associated mechanism. Extensive disruption of the chronically injured secretory acinar-nerve niche can be reversed by muscarinic agonism, with the tissue maintaining a homeostatic-like state months after treatment ends. In addition, the proportion of de-differentiated acinar cell types that appear with chronic damage are greatly reduced by muscarinic stimulation, suggesting recovery of cells critical for function. This reversal is due, in part, to re-balancing a calcium-dependent metabolic pathway that enables cell replacement. Finally, we show that radiation damaged hair follicles also benefit from muscarinic stimulation through a similar mechanism. Thus, these data challenge the concept that chronic damage is irreversible and provide a new avenue for the development of restorative treatments, a paradigm shift that can be explored more broadly. Overall design: To irreversible degeneration that lead to a permanent loss in organ function, we performed transcriptomic analysis of SGs at 30-, 60-, and 90-days post-IR via bulk RNA-sequencing