P38α MAPK Coordinates Mitochondrial Adaptation to Caloric Surplus in Skeletal Muscle
Abstract
:1. Introduction
2. Results
2.1. Mice with Attenuated p38α Activity Develop Metabolic Syndrome and Exhibit Decreased Insulin Sensitivity Relative to Wild-Type Mice
2.2. The Muscles of p38αAF Mice Display Compromised Insulin Signaling and Resistance to Insulin-Mediated Glucose Uptake
2.3. Insulin Fails to Augment Glycolysis in the Muscles of HFD-Fed p38αAF Mice
2.4. Reduced Fatty Acid Oxidation in the Muscles of p38αAF Mice
2.5. Increased Mitochondrial Damage in the Muscles of p38αAF Mice
2.6. Palmitate Inhibits Glycolysis, Particularly in Myotubes Derived from p38αAF Mice
2.7. Reduced Regulation of Pyruvate Dehydrogenase in the Myotubes of p38αAF Mice
2.8. Elevated Flux of Palmitate Oxidation in the Myotubes of p38αAF Mice
2.9. The Myotubes from p38αAF Mice Exhibited Lower Mitochondrial Capacity Compared to the Control Myotubes
3. Discussion
3.1. P38α Mouse Model
3.2. Metabolomics
3.3. P38α and Insulin Sensitivity
3.4. P38α Regulation of β Oxidation
3.5. The Role of p38α in Mitochondrial Metabolic Flexibility
3.6. The Proposed Model
4. Materials and Methods
4.1. Animal Ethics
4.2. Animal Model
4.3. HFD-Induced Obesity and Insulin Resistance
4.4. Protein Extraction and Western Blot Analysis
4.5. Quantitative Real-Time PCR (qRT-PCR)
4.6. Targeted Metabolomics and Stable Isotope Tracing Analysis by LC-MS
4.6.1. Sample Preparation
4.6.2. LC-MS Data Acquisition
4.6.3. Metabolomics Data Analysis
4.7. Myotube Cell Culture
4.8. “Seahorse” Analysis of the Oxygen Consumption Rate (OCR) and Extracellular Acidification Rate (ECAR)
4.9. Detection of JC-1 Fluorescence
4.10. Electron Microscopy
4.11. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
MAPK | Mitogen-activated protein kinase |
PDH | Pyruvate dehydrogenase |
ACC2 | Acetyl CoA Carboxylase 2 |
ND | Balanced chow diet |
HFD | High-fat diet |
LCFA | Long-chain fatty acid |
CPT1 | Carnitine palmitoyltransferase 1 |
Tb | Tibialis anterior |
TCA | Tricarboxylic acid |
AMPK | AMP-activated protein kinase |
PGC-1α | Peroxisome proliferator-activated receptor gamma coactivator 1-alpha |
ITT | Insulin tolerance test |
ROS | Reactive oxygen species |
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Waingerten-Kedem, L.; Aviram, S.; Blau, A.; Hayek, T.; Bengal, E. P38α MAPK Coordinates Mitochondrial Adaptation to Caloric Surplus in Skeletal Muscle. Int. J. Mol. Sci. 2024, 25, 7789. https://doi.org/10.3390/ijms25147789
Waingerten-Kedem L, Aviram S, Blau A, Hayek T, Bengal E. P38α MAPK Coordinates Mitochondrial Adaptation to Caloric Surplus in Skeletal Muscle. International Journal of Molecular Sciences. 2024; 25(14):7789. https://doi.org/10.3390/ijms25147789
Chicago/Turabian StyleWaingerten-Kedem, Liron, Sharon Aviram, Achinoam Blau, Tony Hayek, and Eyal Bengal. 2024. "P38α MAPK Coordinates Mitochondrial Adaptation to Caloric Surplus in Skeletal Muscle" International Journal of Molecular Sciences 25, no. 14: 7789. https://doi.org/10.3390/ijms25147789