Related Experiment Video

Updated: Jan 9, 2026

Measurement of Insulin- and Contraction-Stimulated Glucose Uptake in Isolated and Incubated Mature Skeletal Muscle from Mice
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Measurement of Insulin- and Contraction-Stimulated Glucose Uptake in Isolated and Incubated Mature Skeletal Muscle from Mice

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Negative Impact of p21-Activated Kinase 4-Mediated AMP-Activated Protein Kinase Inhibition on Sarcopenia in Mice and

Jiacheng Du1, Hwang Chan Yu2, Young Jae Moon1,3

  • 1Department of Biochemistry and Molecular Biology Jeonbuk National University Medical School Jeonju Republic of Korea.

Medcomm
|December 2, 2025
PubMed

Insights

p21-activated kinase 4 (PAK4) drives muscle atrophy by phosphorylating AMP-activated protein kinase (AMPK) at S491. Inhibiting PAK4 protects against muscle loss and mitochondrial dysfunction, offering therapeutic potential for sarcopenia.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Physiology

Background:

  • AMP-activated protein kinase (AMPK) α2 phosphorylation at S491 by p21-activated kinase 4 (PAK4) is linked to insulin resistance.
  • Muscle atrophy is a significant issue in chronic disease and aging, with limited therapeutic options.

Purpose of the Study:

  • To investigate the role of muscle PAK4 in muscle atrophy.
  • To explore the therapeutic potential of targeting PAK4 for muscle atrophy.

Main Methods:

  • Utilized muscle-specific Pak4 knockout mice and dexamethasone/denervation-induced atrophy models.
  • Administered a proteolysis-targeting chimera (PROTAC) to inhibit PAK4.
  • Analyzed gene expression, protein levels, mitochondrial function, and AMPK phosphorylation (S491).
  • Compared PAK4 and AMPKα2-S491 phosphorylation levels in human sarcopenic muscle versus controls.

Main Results:

  • Muscle-specific Pak4 knockout mice were protected from dexamethasone- and denervation-induced muscle atrophy.
  • PAK4 inhibition via PROTAC mitigated muscle atrophy, improved mitochondrial function, and enhanced biogenesis gene expression.
  • PAK4 inhibition reduced AMPKα2-S491 phosphorylation, while phospho-deficient AMPKα2S491A preserved muscle mass.
  • Sarcopenic human muscle showed elevated PAK4 and AMPKα2-S491 phosphorylation, inversely correlating with muscle function.

Conclusions:

  • PAK4 regulates muscle mass and mitochondrial function through AMPKα2-S491 phosphorylation.
  • Targeting PAK4 presents a promising therapeutic strategy for muscle atrophy associated with aging and disease.
  • This study identifies a novel mechanism linking PAK4, AMPK, and muscle health.
Keywords:
AMPKmitochondriamuscle atrophyp21‐activated kinase 4proteolysis‐targeting chimera

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