TWIST1 and TWIST2 regulate glycogen storage and inflammatory genes in skeletal muscle

Jonathan M Mudry1, Julie Massart1, Ferenc L M Szekeres1

  • 1Section for Integrative PhysiologyDepartment of Molecular Medicine and SurgerySection for Integrative PhysiologyDepartment of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.

Insights

TWIST proteins impact skeletal muscle metabolism by altering glycogen and cytokine levels. However, TWIST gene expression remains unchanged in metabolic diseases like type 2 diabetes.

Area of Science:

  • Molecular biology
  • Metabolism research
  • Skeletal muscle physiology

Background:

  • TWIST proteins are crucial for embryonic development and influence tumor and adipose tissue metabolism.
  • The specific role of TWIST in skeletal muscle metabolism is not well understood.
  • Investigating TWIST's impact on skeletal muscle is vital for understanding metabolic regulation.

Purpose of the Study:

  • To determine the effects of TWIST1 and TWIST2 overexpression on glucose and lipid metabolism in skeletal muscle.
  • To analyze the molecular changes associated with TWIST overexpression in muscle tissue.
  • To examine TWIST transcript levels in the context of metabolic disease and exercise.

Main Methods:

  • Overexpression of TWIST1 and TWIST2 in intact mouse muscle and C2C12 myoblast cells.
  • Analysis of glucose uptake, glycogen content, and fatty acid oxidation.
  • Measurement of mRNA levels for key metabolic and inflammatory genes (e.g., Pdk4, Il6, Tnfα, Il1β).
  • Assessment of protein phosphorylation (AKT) and abundance (ACC).
  • Examination of TWIST mRNA levels in ob/ob mice, type 2 diabetic patients, and healthy individuals.

Main Results:

  • TWIST overexpression in mouse muscle reduced total glycogen but did not affect glucose uptake.
  • TWIST1/TWIST2 expression altered mRNA levels of inflammatory cytokines (Il6, Tnfα, Il1β) and reduced Pdk4 mRNA.
  • Increased AKT phosphorylation and decreased acetyl CoA carboxylase (ACC) protein were observed with TWIST overexpression.
  • Glycogen synthesis and fatty acid oxidation were unaffected in C2C12 cells overexpressing TWIST1/TWIST2.
  • Skeletal muscle TWIST mRNA levels were unchanged in models of metabolic disease and after exercise training.

Conclusions:

  • TWIST1 and TWIST2 are present in skeletal muscle and influence metabolic and inflammatory pathways upon overexpression.
  • Overexpression of TWIST proteins affects key metabolic regulators and cytokine signaling in muscle.
  • Skeletal muscle TWIST transcript levels do not appear to be altered in conditions of metabolic dysfunction or in response to exercise.

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