RT Journal Article
SR Electronic
T1 PTPN1/2 inhibition promotes muscle stem cell differentiation in Duchenne muscular dystrophy
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202402831
DO 10.26508/lsa.202402831
VO 8
IS 1
A1 Liu, Yiyang
A1 Li, Shulei
A1 Robertson, Rebecca
A1 Granet, Jules A
A1 Aubry, Isabelle
A1 Filippelli, Romina L
A1 Tremblay, Michel L
A1 Chang, Natasha C
YR 2025
UL http://www.life-science-alliance.org/content/8/1/e202402831.abstract
AB Duchenne muscular dystrophy (DMD) is a lethal disease caused by mutations in the DMD gene that encodes dystrophin. Dystrophin deficiency also impacts muscle stem cells (MuSCs), resulting in impaired asymmetric stem cell division and myogenic commitment. Using MuSCs from DMD patients and the DMD mouse model mdx, we found that PTPN1 phosphatase expression is up-regulated and STAT3 phosphorylation is concomitantly down-regulated in DMD MuSCs. To restore STAT3-mediated myogenic signaling, we examined the effect of K884, a novel PTPN1/2 inhibitor, on DMD MuSCs. Treatment with K884 enhanced STAT3 phosphorylation and promoted myogenic differentiation of DMD patient-derived MuSCs. In MuSCs from mdx mice, K884 treatment increased the number of asymmetric cell divisions, correlating with enhanced myogenic differentiation. Interestingly, the pro-myogenic effect of K884 is specific to human and murine DMD MuSCs and is absent from control MuSCs. Moreover, PTPN1/2 loss-of-function experiments indicate that the pro-myogenic impact of K884 is mediated mainly through PTPN1. We propose that PTPN1/2 inhibition may serve as a therapeutic strategy to restore the myogenic function of MuSCs in DMD.All data underlying the research presented in the manuscript are available in the published article and its online supplemental material.