PTPN1/2 inhibition promotes muscle stem cell differentiation in Duchenne muscular dystrophy

Life Sci Alliance. 2024 Oct 30;8(1):e202402831. doi: 10.26508/lsa.202402831. Print 2025 Jan.

Abstract

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.

MeSH terms

  • Animals
  • Cell Differentiation* / drug effects
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Inbred mdx*
  • Muscle Development / drug effects
  • Muscle Development / genetics
  • Muscle, Skeletal / metabolism
  • Muscular Dystrophy, Duchenne* / genetics
  • Muscular Dystrophy, Duchenne* / metabolism
  • Muscular Dystrophy, Duchenne* / pathology
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1* / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1* / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1* / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2* / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2* / metabolism
  • STAT3 Transcription Factor* / metabolism
  • Signal Transduction / drug effects
  • Stem Cells / cytology
  • Stem Cells / metabolism

Substances

  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2
  • STAT3 Transcription Factor
  • PTPN1 protein, human
  • PTPN2 protein, human