Presenilin-1 acts via Id1 to regulate the function of muscle satellite cells in a gamma-secretase-independent manner.

Muscle satellite cells are the resident stem cells of adult skeletal muscle. Here, we have examined the role of the multifunctional protein presenilin-1 (PS1) in satellite cell function. PS1 acts as a crucial component of the gamma-secretase complex, which is required to cleave single-pass transmembrane proteins such as Notch and amyloid-beta precursor protein. PS1, however, also functions through gamma-secretase-independent pathways. Activation of satellite cells was accompanied by induction of PS1, with PS1 knockdown enhancing their myogenic differentiation, but reducing their self-renewal. Transfection with siRNA against PS1 led to accelerated myogenic differentiation during muscle regeneration in vivo. Conversely, constitutive expression of PS1 resulted in the suppression of myogenic differentiation and promotion of the self-renewal phenotype. Importantly, we found that PS1 also acts independently of its role in gamma-secretase activity in controlling myogenesis, which is mediated in part by Id1 (inhibitor of DNA binding 1), a negative regulator of the myogenic regulatory factor MyoD. PS1 can control Id1, which affects satellite cell fate by regulating the transcriptional activity of MyoD. Taken together, our observations show that PS1 is a key player in the choice of satellite cell fate, acting through both gamma-secretase-dependent and gamma-secretase-independent mechanisms.