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Toward Ameliorating Insulin Resistance: Targeting a Novel PAK1 Signaling Pathway Required for Skeletal Muscle

Rekha Balakrishnan1, Pablo A Garcia1, Rajakrishnan Veluthakal1

  • 1Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Beckman Research Institute, 1500 E Duarte Road, Duarte, CA 91010, USA.

Antioxidants (Basel, Switzerland)
|September 28, 2023
PubMed

Insights

p21-activated kinase 1 (PAK1) regulates skeletal muscle mitochondrial function and insulin sensitivity. PAK1 depletion impairs mitochondrial respiration and PGC1α expression, while its enrichment improves these functions, suggesting PAK1 is upstream of the p38MAPK/ATF2/PGC1α pathway.

Area of Science:

  • Cell Biology
  • Metabolism
  • Molecular Biology

Background:

  • p21-activated kinase 1 (PAK1) is crucial for insulin-stimulated glucose uptake in skeletal muscle.
  • The role of PAK1 in regulating skeletal muscle mitochondrial function, a key factor in insulin sensitivity, remains unclear.

Purpose of the Study:

  • To investigate the effect of modulating PAK1 on mitochondrial function in skeletal muscle cells.
  • To elucidate the signaling pathway through which PAK1 influences mitochondrial biogenesis and oxidative metabolism.

Main Methods:

  • PAK1 levels were modulated using siRNA (knockdown) and adenoviral transduction (overexpression) in rat L6.GLUT4myc and human LHCN-M2 myotubes.
  • Mitochondrial function, including copy number and respiration, was assessed.
  • Expression of PGC1α, p38MAPK, and ATF2 was analyzed.
  • Experiments included insulin-resistant myotubes and human type 2 diabetes (T2D) and non-diabetic (ND) skeletal muscle samples.

Main Results:

  • PAK1 depletion decreased mitochondrial copy number, respiration, and PGC1α expression, alongside its activators p38MAPK and ATF2.
  • PAK1 enrichment in insulin-resistant myotubes improved mitochondrial function and restored PGC1α levels.
  • PAK1 activity was localized to the cytoplasm, and its enrichment did not rescue PGC1α levels when p38MAPK was inhibited.
  • Human T2D samples showed reduced PGC1α, and PAK1 depletion in human myotubes decreased mitochondrial respiration.

Conclusions:

  • PAK1 plays a significant role in regulating skeletal muscle mitochondrial function.
  • PAK1 acts upstream of the p38MAPK/ATF2/PGC1α pathway to control mitochondrial biogenesis and oxidative metabolism.
  • Modulating PAK1 activity may represent a therapeutic target for improving insulin sensitivity in conditions like type 2 diabetes.
Keywords:
PAK1insulin resistancemitochondriaskeletal muscletype 2 diabetes

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