Experimental and Molecular Medicine (Apr 2024)

Transcriptome-based deep learning analysis identifies drug candidates targeting protein synthesis and autophagy for the treatment of muscle wasting disorder

  • Min Hak Lee,
  • Bada Lee,
  • Se Eun Park,
  • Ga Eul Yang,
  • Seungwoo Cheon,
  • Dae Hoon Lee,
  • Sukyeong Kang,
  • Ye Ji Sun,
  • Yongjin Kim,
  • Dong-sub Jung,
  • Wonwoo Kim,
  • Jihoon Kang,
  • Yi Rang Kim,
  • Jin Woo Choi

DOI
https://doi.org/10.1038/s12276-024-01189-z
Journal volume & issue
Vol. 56, no. 4
pp. 904 – 921

Abstract

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Abstract Sarcopenia, the progressive decline in skeletal muscle mass and function, is observed in various conditions, including cancer and aging. The complex molecular biology of sarcopenia has posed challenges for the development of FDA-approved medications, which have mainly focused on dietary supplementation. Targeting a single gene may not be sufficient to address the broad range of processes involved in muscle loss. This study analyzed the gene expression signatures associated with cancer formation and 5-FU chemotherapy-induced muscle wasting. Our findings suggest that dimenhydrinate, a combination of 8-chlorotheophylline and diphenhydramine, is a potential therapeutic for sarcopenia. In vitro experiments demonstrated that dimenhydrinate promotes muscle progenitor cell proliferation through the phosphorylation of Nrf2 by 8-chlorotheophylline and promotes myotube formation through diphenhydramine-induced autophagy. Furthermore, in various in vivo sarcopenia models, dimenhydrinate induced rapid muscle tissue regeneration. It improved muscle regeneration in animals with Duchenne muscular dystrophy (DMD) and facilitated muscle and fat recovery in animals with chemotherapy-induced sarcopenia. As an FDA-approved drug, dimenhydrinate could be applied for sarcopenia treatment after a relatively short development period, providing hope for individuals suffering from this debilitating condition.