P38α MAPK Coordinates Mitochondrial Adaptation to Caloric Surplus in Skeletal Muscle
<p>p38α<sup>AF</sup> mice presented worse metabolic parameters than control mice. (<b>A</b>) Six-week-old mice were fed with ND or an HFD for 10 weeks, and GC muscles were isolated (<span class="html-italic">n</span> = 5) from the control and p38α<sup>AF</sup> mice. Protein lysates from three of the mice per treatment were randomly analyzed by Western blotting with the designated antibodies. α Tubulin was used as the loading control. The quantification of relative p38α phosphorylation is presented in the histogram. (<b>B</b>) The mice underwent the diets described in (A), and the weight of each mouse was measured weekly (<span class="html-italic">n</span> = 5). The graphs represent the average percent change in the body weight of the two mouse groups (control and p38α<sup>AF</sup>), which were fed with ND or HFD. The weight was set to 100 on the first day of the diet. (<b>C</b>) The hematological parameters of control mice and p38α<sup>AF</sup> on an HFD. The glucose and cholesterol levels were measured in the serum of control and p38α<sup>AF</sup> mice after 10 weeks on an HFD (AML-central lab services). Insulin was measured (<span class="html-italic">n</span> = 3) using an ELISA kit (Millipore RAB0817). The significance probabilities between treatments were designated as numbers. (<b>D</b>) Insulin tolerance test (ITT): the graph displays the relative average glucose levels at 0, 30, 45, 60, 90, and 120 min following insulin injection (0.5 U/kg BW) in the blood of control and p38α<sup>AF</sup> mice after a 10-week HFD (<span class="html-italic">n</span> = 4 mice per group). The mice were deprived of chaw for 6 h before insulin was IP-injected. The glucose level before insulin injection was set to 100 percent, and all values were relative to 100. Data are presented as the mean ± SE. One-way ANOVA was followed by Tukey post-tests (<b>A</b>), two-way ANOVA was followed by Bonferroni post-tests (<b>B</b>,<b>D</b>) and a Student t-test (<b>C</b>). The <span class="html-italic">p</span> values for group difference are designated as follows: * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, and *** <span class="html-italic">p</span> < 0.001.</p> "> Figure 2
<p>Block of the insulin-mediated 2 deoxy-glucose (2DG) uptake by the Tibialis muscle of p38α<sup>AF</sup> mice. (<b>A</b>) Experimental layout: saline or insulin (1 unit/kg) was IP-injected following a 3 h fasting of the mice previously fed with an HFD for 10 weeks. Ten min later, 5% 2DG was IP-injected (10 μL to 1 g weight). The mice were sacrificed one hour later, and the Tibialis muscles were frozen and used in the mass spectrometry (MS) analysis of metabolites, or to extract proteins for Western blotting analysis. (<b>B</b>) Peak area were analyzed by the MS values of 2- Deoxy –D Glucose (<span class="html-italic">n</span> = 4) that were normalized to mg tissue. (<b>C</b>) Protein extracts from the Tb muscles (<span class="html-italic">n</span> = 3) were analyzed by Western blotting with antibodies directed to phosphorylated Akt (Serine 473) and Pan Akt. Quantification of the relative phosphorylation (pAkt/Akt) is presented in the histogram. Data are presented as the mean ± SE. The Wilcoxon test and significance probabilities between treatments are designated as numbers in (<b>B</b>). One-way ANOVA was followed by Tukey post-tests. The <span class="html-italic">p</span> values for group difference are designated as follows: * <span class="html-italic">p</span> < 0.05 (<b>C</b>).</p> "> Figure 3
<p>Reduced glycolytic metabolites and increased lactate-to-pyruvate ratio in the muscles of HFD-fed p38α<sup>AF</sup> mice. Extracted metabolites from the Tibialis muscles of 10-week HFD-fed mice that were IP-injected without or with insulin (<span class="html-italic">n</span> = 4). (<b>A</b>) The normalized peak areas (to mg tissue) that were analyzed by the MS of several glycolytic metabolites. (<b>B</b>) The normalized peak areas (to mg tissue) that were analyzed by the MS of pyruvate, lactate, and the ratio of lactate to pyruvate. (<b>C</b>) Analysis of the expression and the phosphorylation on serine 293 of the E1 subunit of pyruvate dehydrogenase (PDH) in the Tb muscles of control and p38α<sup>AF</sup> mice (<span class="html-italic">n</span> = 5) by Western blotting using antibodies to phospho-PDH (Ser293) and PDH. The quantification of relative phosphorylation (pPDH/PDH) is presented in the histogram. Data are presented as the mean ± SE. The Wilcoxon test and significance probabilities between treatments are designated as numbers in (<b>B</b>).</p> "> Figure 4
<p>Reduced β oxidation in the muscles of p38α<sup>AF</sup> mice relative to the muscles of control mice following a high-fat diet. Metabolites were extracted from the Tibialis muscles of 10-week HFD-fed mice that were IP-injected without or with insulin (<span class="html-italic">n</span> = 4). (<b>A</b>) The peak areas (normalized to mg tissue) of glycerol analyzed by MS are presented. (<b>B</b>) Analysis of the mRNA levels of FABP3 in the muscles of control and p38α<sup>AF</sup> mice by qPCR (<span class="html-italic">n</span> = 5). The β-actin housekeeping gene was used to normalize the mRNA levels. (<b>C</b>) Analysis of the mRNA levels of ACC2 in the muscles of control and p38α<sup>AF</sup> mice by qPCR (<span class="html-italic">n</span>= 4). The β-actin housekeeping gene was used to normalize mRNA levels. (<b>D</b>) Analysis of the expression and the phosphorylation on serine 212 of Acetyl CoA Carboxylase 2 (ACC2) in the muscles of control and p38α<sup>AF</sup> mice (<span class="html-italic">n</span> = 5) by Western blotting using antibodies to phospho-ACC2 (Ser212), ACC2, and αTubulin (which served as a loading control). The histograms present the relative expression of ACC2 (ACC2/Tubulin) and relative ACC2 phosphorylation on serine 212 (pACC2/ACC2). (<b>E</b>) The peak areas (normalized to mg tissue) of acyl-carnitines are presented. Values represent the means ± SEM. The Wilcoxon test and significance probabilities between treatments are designated as numbers (<b>A</b>,<b>E</b>). One-way ANOVA followed by Tukey post-tests (<b>B</b>,<b>C</b>). The <span class="html-italic">p</span> values for group difference are designated as follows: * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, and *** <span class="html-italic">p</span> < 0.001.</p> "> Figure 5
<p>Severe mitochondrial defects in the muscles of p38α<sup>AF</sup> mice. (<b>A</b>) Transmission electron microscopy (TEM) analysis of the representative muscles from control and p38α<sup>AF</sup> mice fed with NDs and HFDs. The Tibialis muscles were isolated, and longitudinal sections were processed for TEM analysis (see <a href="#sec4dot10-ijms-25-07789" class="html-sec">Section 4.10</a>). Representative images are shown. Scale bar: 1 μm. Asterisks are adjacent to the mitochondria (<b>B</b>) Analysis of the mRNA levels of PGC1α in the muscles of control and p38α<sup>AF</sup> mice fed with NDs and HFDs by qPCR (<span class="html-italic">n</span> = 5). The β-actin housekeeping gene was used to normalize the mRNA levels. Data represent the means ± SEM. One-way ANOVA was followed by Tukey post-tests (B). The <span class="html-italic">p</span> values for group differences are designated as follows: * <span class="html-italic">p</span> < 0.05.</p> "> Figure 6
<p>Biochemical and metabolic analysis of the myotubes derived from control and p38α<sup>AF</sup> mice. (<b>A</b>) p38 MAPK phosphorylation: Myotubes were grown for 24 h in the absence or presence of 0.4 mM of palmitate. Insulin (10 μg/mL) was added 30 min before the proteins were extracted and analyzed by Western blotting using the designated antibodies. (<b>B</b>) Insulin signaling pathway: The same protein samples as in (A) were analyzed by Western blotting using the designated antibodies. (<b>C</b>) Metabolism of the (U-<sup>13</sup>C<sub>6</sub>) glucose in myotubes: (U-<sup>13</sup>C<sub>6</sub>) glucose was introduced to the myotube media with or without 0.4 mM of palmitate for 24 h. The relative levels of glucose 6-phosphate (+6), fructose 6-phosphate (+6), and ribose phosphate (+5) isotopologues are presented. The peak area was normalized to protein concentration. (<b>D</b>) Medium acidification (ECAR) of myotubes in a “Seahorse” analysis: Myotubes were grown in glucose, or glucose and palmitate, for 24 h before analysis. (<b>E</b>) Metabolism of the (U-<sup>13</sup>C<sub>6</sub>) glucose in myotubes: The relative levels of the isotopologues of citrate are presented. The peak areas were normalized to protein concentration. (<b>F</b>) Mitochondrial enzymes: The same protein samples as in (A) were analyzed by Western blotting. The histograms present the relative expression and phosphorylation of PDH (Ser293), and the expression of citrate synthase. Data represent the means ± SEM. The Wilcoxon test and significance probabilities between treatments are designated as follows: * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, and *** <span class="html-italic">p</span> < 0.001 (<b>C</b>,<b>E</b>). One-way ANOVA was followed by Tukey post-tests (<b>D</b>). The <span class="html-italic">p</span> values for group differences are designated as follows: * <span class="html-italic">p</span> < 0.05 and *** <span class="html-italic">p</span> < 0.001.</p> "> Figure 7
<p>Metabolism of palmitate in the myotubes derived from control and p38α<sup>AF</sup> mice. Myotubes were grown in a low-glucose DMEM supplemented with 0.4 mM of palmitate-<sup>13</sup>C<sub>16</sub> for 6 and 24 h. (<b>A</b>) The peak area (normalized to protein concentration) of palmitate (+16), the isotopologues of the TCA cycle, and the derived amino acids that originated from palmitate-<sup>13</sup>C<sub>16.</sub> FC: fold change in the palmitate derived (<sup>13</sup>C ≥ 2) metabolite abundance relative to a WT of 6 h or WT of 24 h. Dashed arrows indicate of missing stages in the TCA-cycle. (<b>B</b>) Myotubes were grown for 24 h in the absence or presence of 0.4 mM of palmitate. Insulin (10 μg/mL) was added 30 min before proteins were extracted and analyzed by Western blotting with the designated antibodies. The histograms present the relative expression of ACC2, the phosphorylation of ACC2 (Ser212), and the phosphorylation of AMPKα (Thr172). (<b>C</b>) The oxygen consumption rate (OCR) at the maximal respiration of myotubes that were grown on glucose, or glucose and palmitate, for 24 h. (<b>D</b>) Comparison of the mitochondrial membrane electrochemical potential in myotubes that were grown on glucose, or glucose and palmitate, for 24 h. JC-1 dye was used to monitor the mitochondrial membrane potential. FCCP disrupts the mitochondrial membrane potential. Data represent the means ± SEM. One-way ANOVA was followed by Tukey post-tests (<b>A</b>,<b>C</b>). The <span class="html-italic">p</span> values for group difference are designated as follows: * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, and *** <span class="html-italic">p</span> < 0.001.</p> "> Figure 8
<p>A model for the role of p38α in insulin sensitivity. In the left panel, a high-fat diet activates p38α in wild-type mice, leading to an increased expression and activity of PGC1α and ACC2 in the skeletal muscles. PGC1α acts as a co-activator, increasing mitochondrial biogenesis and activity, while ACC2 regulates fatty acid transport into mitochondria. These activities of p38α help coordinate glucose and fat oxidation, preserving metabolic flexibility and preventing mitochondrial damage. Under these conditions, both energy balance and insulin sensitivity are preserved.</p> ">
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