Chronic Intermittent Hypoxia-Induced Diaphragm Muscle Weakness Is NADPH Oxidase-2 Dependent
Abstract
:1. Introduction
2. Materials and Methods
2.1. Ethical Approval
2.2. Chronic Intermittent Hypoxia Animal Model
2.3. Ex Vivo Muscle Function Analysis
2.3.1. Muscle Dissection and Preparation
2.3.2. Isometric Muscle Function
2.3.3. Isotonic Muscle Function
2.4. Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR)
2.4.1. RNA Extraction and Preparation
2.4.2. cDNA Synthesis
2.4.3. qRT-PCR
2.5. Western Blotting
2.5.1. Protein Extraction and Quantification
2.5.2. Gel Electrophoresis
2.6. Spectrophotometric Assays
2.6.1. Protein Extraction and Quantification
2.6.2. NADPH Oxidase Activity
2.6.3. Citrate Synthase Activity
2.6.4. Thiobarbituric Acid Reactive Substances
2.7. Cell Signalling Assays
2.7.1. Protein Extraction and Quantification
2.7.2. Hypertrophy, Atrophy, and HIF Signalling Assays
2.8. Statistical Analysis
3. Results
3.1. Diaphragm Muscle Contractile Function Ex Vivo
3.2. NOX mRNA and Protein Expression in Diaphragm Muscle
3.3. Indices of Redox Balance, Protein Synthesis and Degradation in Diaphragm Homogenates from Sham and CIH-Exposed Mice
3.4. mRNA Expression of Genes Relating to Myogenesis in Diaphragm Muscle
3.5. mRNA Expression of Genes Relating to Antioxidant Status in Diaphragm Muscle
3.6. mRNA Expression of Genes Relating to Inflammation and Protein Degradation in Diaphragm Muscle
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene Name | Gene Symbol | Assay ID |
---|---|---|
NOX enzymes | ||
NOX1 | NOX1 | 310986 |
NOX2 | Cybb | 317885 |
NOX4 | NOX4 | 300795 |
p22phox | Cyba | 317890 |
p47phox | Ncf1 | 301105 |
p67phox | Ncf2 | 317897 |
p40phox | Ncf4 | 317894 |
Rac | Racgap1 | 310907 |
Duox1 | Duox1 | 317891 |
Duox2 | Duox2 | 317888 |
Atrophy | ||
Atrogin-1 | Fbxo32 | 317844 |
MuRF-1 | Trim63 | 317843 |
Autophagy | ||
BNIP3 | Bnip3 | 311465 |
LC3B | Map1lc3b | 317920 |
GABARAPL1 | Gabarapl1 | 317923 |
Mitophagy | ||
PINK-1 | Pink1 | 331846 |
PARK-2 | Park2 | 317264 |
Inflammation | ||
NFκB | Nfkb1 | 300085 |
Antioxidant | ||
SOD1 | Sod1 | 310738 |
SOD2 | Sod2 | 310295 |
Catalase | Cat | 310718 |
Nrf2 | Nfe2l2 | 313377 |
Muscle differentiation | ||
Myogenin | Myog | 313501 |
Myostatin | Mstn | 318626 |
MyoD | Myod1 | 313570 |
MEF2C | Mef2c | 318629 |
IGF1 | Igf1 | 313359 |
Sirtuin-1 | Sirt1 | 310480 |
Reference | ||
HPRT1 | Hprt1 | 307879 |
Sham (n = 8) | CIH (n = 8) | CIH + APO (n = 9) | One-Way ANOVA | Sham vs. CIH (p Value) | CIH vs. CIH + APO (p Value) | |
---|---|---|---|---|---|---|
Pt (N/cm2) | 2.62 ± 0.90 | 1.63 ± 0.31 | 4.10 ± 1.86 | 0.0021 | 0.2738 | 0.0016 |
CT (ms) | 15.70 ± 0.96 | 16.70 ± 3.87 | 18.17 ± 3.14 | 0.2378 | - | - |
½ RT (ms) | 19.69 ± 7.82 | 19.63 ± 6.39 | 17.50 ± 3.79 | 0.7045 | - | - |
Wmax (J/cm2) | 1.60 ± 0.85 | 0.63 ± 0.21 | 1.69 ± 0.84 | 0.0012 | 0.0060 | 0.0030 |
Pmax (W/cm2) | 14.70 ± 8.13 | 6.57 ± 2.35 | 13.60 ± 4.55 | 0.0142 | 0.0193 | 0.0392 |
Smax (L/L0) | 0.35 ± 0.06 | 0.30 ± 0.08 | 0.37 ± 0.07 | 0.1374 | - | - |
Vmax (L0/s) | 4.78 ± 1.57 | 3.59 ± 1.19 | 4.51 ± 0.95 | 0.1403 | - | - |
Muscle mass (mg) | 1.48 ± 0.13 | 1.30 ± 0.21 | 1.47 ± 0.47 | 0.2680 | - | - |
Body mass (g) | 23.6 ± 1.5 | 21.4 ± 0.7 | 23.5 ± 1.6 | 0.0014 | 0.0032 | 0.0047 |
NOX2 KO Sham (n = 9) | NOX2 KO CIH (n = 9) | NOX2 KO Sham vs. NOX2 KO CIH (p Value) | |
---|---|---|---|
Pt (N/cm2) | 3.50 ± 2.30 | 5.52 ± 2.75 | 0.1107 |
CT (ms) | 12.28 ± 2.00 | 12.44 ± 1.67 | 0.8502 |
½ RT (ms) | 13.39 ± 5.41 | 12.56 ± 5.04 | 0.8482 |
Wmax (J/cm2) | 2.42 ± 0.67 | 2.16 ± 0.38 | 0.3923 |
Pmax (W/cm2) | 18.74 ± 4.61 | 15.57 ± 5.02 | 0.1821 |
Smax (L/L0) | 0.40 ± 0.05 | 0.36 ± 0.04 | 0.1148 |
Vmax (L0/s) | 4.53 ± 1.39 | 3.98 ± 1.27 | 0.3958 |
Muscle mass (mg) | 2.01 ± 0.89 | 1.66 ± 0.39 | 0.2866 |
Body mass (g) | 28.1 ± 2.5 | 25.4 ± 0.9 | 0.0042 |
Sham (n = 8) | CIH (n = 8) | Sham vs. CIH (p Value) | |
---|---|---|---|
NADPH Oxidase Activity (nmol/min/µg) | 0.26 ± 0.09 | 0.29 ± 0.06 | 0.5565 |
TBARS (nM/mg) | 193.2 ± 93.18 | 151.6 ± 79.53 | 0.3536 |
Citrate Synthase Activity (µmole/mg) | 0.68 ± 0.20 | 0.63 ± 0.22 | 0.5892 |
HIF-1α (signal/µg) | 2.73 ± 0.48 | 2.62 ± 0.34 | 0.5982 |
Phospho-FOXO-3a (signal/µg) | 72.81 ± 19.59 | 63.27 ± 18.09 | 0.3284 |
Phopho-ERK1/2 (signal/µg) | 54.49 ± 18.05 | 41.43 ± 17.61 | 0.0379 |
Phospho-JNK (signal/µg) | 61.15 ± 10.34 | 48.25 ± 10.82 | 0.0287 |
Phospho-p38 (signal/µg) | 13.83 ± 1.18 | 11.36 ± 1.10 | 0.0007 |
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Drummond, S.E.; Burns, D.P.; El Maghrani, S.; Ziegler, O.; Healy, V.; O’Halloran, K.D. Chronic Intermittent Hypoxia-Induced Diaphragm Muscle Weakness Is NADPH Oxidase-2 Dependent. Cells 2023, 12, 1834. https://doi.org/10.3390/cells12141834
Drummond SE, Burns DP, El Maghrani S, Ziegler O, Healy V, O’Halloran KD. Chronic Intermittent Hypoxia-Induced Diaphragm Muscle Weakness Is NADPH Oxidase-2 Dependent. Cells. 2023; 12(14):1834. https://doi.org/10.3390/cells12141834
Chicago/Turabian StyleDrummond, Sarah E., David P. Burns, Sarah El Maghrani, Oscar Ziegler, Vincent Healy, and Ken D. O’Halloran. 2023. "Chronic Intermittent Hypoxia-Induced Diaphragm Muscle Weakness Is NADPH Oxidase-2 Dependent" Cells 12, no. 14: 1834. https://doi.org/10.3390/cells12141834