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Twist1 Activation in Muscle Progenitor Cells Causes Muscle Loss Akin to Cancer Cachexia

Parash Parajuli1, Santosh Kumar1, Audrey Loumaye2

  • 1Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA.

Developmental Cell
|June 20, 2018
PubMed

Insights

Twist1 overexpression in muscle causes severe muscle loss, mimicking cancer cachexia. Inhibiting Twist1 in muscle progenitor cells protected against cachexia and improved survival in mouse models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Muscle Physiology

Background:

  • Cancer cachexia involves significant skeletal muscle loss, leading to high mortality.
  • Pancreatic ductal adenocarcinoma (PDAC) frequently causes severe weight loss in patients.
  • The mechanisms driving tumor-induced muscle depletion are not fully understood.

Purpose of the Study:

  • To investigate the role of Twist1 in muscle progenitor cells in the development of cancer cachexia.
  • To determine if targeting Twist1 could be a therapeutic strategy for cancer cachexia.

Main Methods:

  • Overexpression of Twist1 in mouse muscle progenitor cells (developmentally and inducibly).
  • Utilized genetic mouse models of PDAC.
  • Assessed muscle atrophy and cachexia features.
  • Examined Twist1 expression in human cancer patients with muscle wasting.
  • Genetically and pharmacologically inactivated Twist1 in muscle progenitor cells.

Main Results:

  • Constitutive or inducible Twist1 overexpression in mouse muscle progenitor cells induced severe muscle atrophy resembling cachexia.
  • PDAC mouse models showed increased Twist1 expression in atrophied muscle.
  • Elevated Twist1 levels correlated with muscle wasting in cancer patients.
  • Twist1 inhibition in muscle progenitor cells provided protection against cancer-mediated cachexia and improved survival in mice.

Conclusions:

  • Twist1 plays a critical role in mediating cancer-induced skeletal muscle loss.
  • Targeting Twist1 in muscle progenitor cells offers a potential therapeutic avenue for combating cancer cachexia and improving patient survival.
Keywords:
Activin/Myostatin cytokinesSmad signalingTwist1cancer cachexiamuscle cachexiamuscle progenitor cellsmuscle protein breakdownpancreatic ductal adenocarcinoma

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