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.
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.
Original language | English |
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Pages (from-to) | 12-23 |
Number of pages | 12 |
Journal | Molecular Metabolism |
Volume | 16 |
Early online date | 25 Jul 2018 |
DOIs | |
Publication status | Published - 1 Oct 2018 |
Bibliographical note
The Strategic Research Program in Diabetes at Karolinska Institutet (2009-1068), European Research Council Ideas Program (ICEBERG, ERC-2008-AdG23285), Swedish Research Council (2011-3550), Swedish Diabetes Foundation (DIA2012-082; DIA2012-047), Swedish Foundation for Strategic Research (SRL10-0027), Diabetes Wellness Sweden (2949/2014SW), Novo Nordisk Foundation and Stockholm County Council (NNF14OC0011493 and 20150326) supported this research. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Foundation. Håkan Karlsson and Petter Alm assisted with the initial collection and analysis of biopsies from our human participants. Nicolas Pillon and Jonathon Smith assisted with assay development and data collection, respectively and are affiliated with Department of Physiology and Pharmacology, Integrative Physiology, Karolinska Institutet, Stockholm, Sweden. Florian Salomons assisted with confocal microscopy and is affiliated with the Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.Keywords
- AMPK
- Skeletal muscle
- GDAP1
- Diabetes
- Circadian
- Mitochondria
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Brendan Gabriel
- School of Medicine, Medical Sciences & Nutrition, The Rowett Institute of Nutrition and Health - Research Fellow
- School of Medicine, Medical Sciences & Nutrition, Aberdeen Cardiovascular and Diabetes Centre
Person: Academic Related - Research