Elsevier

Molecular Metabolism

Volume 16, October 2018, Pages 12-23
Molecular Metabolism

Original Article
AMPK activation negatively regulates GDAP1, which influences metabolic processes and circadian gene expression in skeletal muscle

https://doi.org/10.1016/j.molmet.2018.07.004Get rights and content
Under a Creative Commons license
open access

Highlights

  • Transcriptomic studies reveal GDAP1 mRNA is inversely associated with AMPK activity.

  • GDAP1 silencing increases mitochondrial protein abundance in skeletal muscle.

  • GDAP1 silencing influences expression of core molecular clock machinery.

  • GDAP1 is a AMPK target involved in metabolism and circadian gene expression.

Abstract

Objective

We sought to identify AMPK-regulated genes via bioinformatic analysis of microarray data generated from skeletal muscle of animal models with genetically altered AMPK activity. We hypothesized that such genes would play a role in metabolism. Ganglioside-induced differentiation-associated protein 1 (GDAP1), a gene which plays a role in mitochondrial fission and peroxisomal function in neuronal cells but whose function in skeletal muscle is undescribed, was identified and further validated. AMPK activation reduced GDAP1 expression in skeletal muscle. GDAP1 expression was elevated in skeletal muscle from type 2 diabetic patients but decreased after acute exercise.

Methods

The metabolic impact of GDAP1 silencing was determined in primary skeletal muscle cells via siRNA-transfections. Confocal microscopy was used to visualize whether silencing GDAP1 impacted mitochondrial network morphology and membrane potential.

Results

GDAP1 silencing increased mitochondrial protein abundance, decreased palmitate oxidation, and decreased non-mitochondrial respiration. Mitochondrial morphology was unaltered by GDAP1 silencing. GDAP1 silencing and treatment of cells with AMPK agonists altered several genes in the core molecular clock machinery.

Conclusion

We describe a role for GDAP1 in regulating mitochondrial proteins, circadian genes, and metabolic flux in skeletal muscle. Collectively, our results implicate GDAP1 in the circadian control of metabolism.

Keywords

AMPK
Skeletal muscle
GDAP1
Diabetes
Circadian
Mitochondria

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