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Antiaging phenotype in skeletal muscle after endurance exercise is associated with the oxidative phosphorylation pathway

Wasin Laohavinij
Wasin Laohavinij
 and 
Apiwat Mutirangura
Apiwat Mutirangura
   | Jan 31, 2017
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Article Category: Original article
Published Online: Jan 31, 2017
Page range: 455 - 471
DOI: https://doi.org/10.5372/1905-7415.0904.415
Keywords
© 2015 Wasin Laohavinij, Apiwat Mutirangura
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Figure 1

The overall methodological framework for the present study. Significant genes common to the exercise and aging groups were analyzed.CU-DREAM = Connection Up-and Down-Regulation Expression Analysis of Microarrays, DAVID = Database for Annotation, Visualization and Integrated Discovery, GSE = Gene Expression Omnibus Series record, KEGG = Kyoto Encyclopedia of Genes and Genomes
The overall methodological framework for the present study. Significant genes common to the exercise and aging groups were analyzed.CU-DREAM = Connection Up-and Down-Regulation Expression Analysis of Microarrays, DAVID = Database for Annotation, Visualization and Integrated Discovery, GSE = Gene Expression Omnibus Series record, KEGG = Kyoto Encyclopedia of Genes and Genomes

Figure 2

Connection Up- and Down-Regulation Expression Analysis of Microarray (CU-DREAM) results: inverse correlation between exercise and aging. A: ORs and 95% CIs for the up–down correlation between exercise and aging. B: ORs and 95% CIs for the down–up correlation between exercise and aging.
Connection Up- and Down-Regulation Expression Analysis of Microarray (CU-DREAM) results: inverse correlation between exercise and aging. A: ORs and 95% CIs for the up–down correlation between exercise and aging. B: ORs and 95% CIs for the down–up correlation between exercise and aging.

Figure 3

Connection Up-and Down-Regulation Expression Analysis of Microarray (CU-DREAM) results: correlation between exercise and aging. A: ORs and 95% CIs for the up–up correlation between exercise and aging. B: ORs and 95% CIs for the down–down correlation between exercise and aging. Ex = exercise
Connection Up-and Down-Regulation Expression Analysis of Microarray (CU-DREAM) results: correlation between exercise and aging. A: ORs and 95% CIs for the up–up correlation between exercise and aging. B: ORs and 95% CIs for the down–down correlation between exercise and aging. Ex = exercise

Lists of in common genes from significant CU-DREAM results comparing downregulation in resistance exercise and downregulation in aging

In common3 (n= 8)2 (n= 165)
GenesATP5C1, CHCHD3, CYCS, DCUN1D5, DLAT, FAM171A1, NEDD1, RXRGACAA2, ACADM, ACADSB, AGPAT1, AIMP1, AIMP2, ANGEL2, ANKH, ASB12, ASPH, ATP2C1, ATP5F1, ATPAF1, BHLHE41, BLMH, BPGM, C11orf74, C14orf142, C16orf72, C21orf33, C6orf136, CALU, CCM2, CD36, CENPV, CHCHD4, CISD1, CMC1, COQ3, COX10, CRADD, CSPP1, CWC27, CYC1, DEXI, DNM1L, DPH2, DPH5, DTNA, DUS4L, DUSP3, DZIP3, EPM2A, ETV6, FAM100B, FAM110B, FAM190B, FAM82B, FBXO3, FH, FKBP1A, FRMD3, FSD2, FZD7, GBAS, GFM1, GFM2, GNPTAB, GOLGA2, GOLGA4, GOSR2, GOT1, GOT2, GRSF1, GTPBP8, HIBADH, HOOK2, HSPA4, IFRD2, ISCA1, KBTBD2, KCTD9, KPNA6, LANCL1, LPIN1, LYPLA1, LYRM5, MAP2K6, MAPKAP1, MFF, MKKS, MLEC, MOCS2, MRPL35, MRPL48, MRPS30, MRS2, MSRB2, MTRF1L, MTX2, MYOZ3, MYPOP, NAMPT, NDUFAF2, NDUFAF4, NEURL2, NMNAT1, NNT, NUDT6, OSBPL3, OXSM, PDHA1, PDSS1, PEX2, PGK1, PIAS2, PPARGC1A, PPIF, PPP2R3C, PRDX3, PRKAR2A, PSME4, PTCD3, PTPLA, PYROXD1, RABEP1, RABGGTB, RAVER2, RCHY1, RGS3, RNF144A, RPS6KC1, RWDD1, S100A1, SCYL2, SDHC, SDHD, SHISA4, SIRT5, SLC25A15, SLC25A4, SLC25A44, SLC25A46, SMAP1, SNTB1, SOBP, SRF, STAMBP, STRADB, SUCLA2, SYNGR1, TATDN1, TBC1D14, TEF, TFRC, TMTC4, TOMM40L, TOR3A, TPI1, TTN, TUBA3C, UBE2V1, UBP1, UCHL3, ULK2, UQCRB, UQCRH, USP38, UXS1, VLDLR, WIPI1, WSB2, WWP1, ZC3H8, ZNF438

Demographic data for the exercise and aging groups

Exercise group GSE Type8479

Experimental results were measured before and after training from the same individuals for a specific duration.

 Resistance exercise		9103

Experimental results were measured from 2 defined sample groups (active/inactive).

 Endurance exercise		16907

Experimental results were measured before and after training from the same individuals for a specific duration.

 Power training		20319

Experimental results were measured from 2 defined sample groups (active/inactive).

 Physically active		Aging group GSE
Duration of exercise6 months4 years12 months32 years8014288479910338718
Experimental group

Experimental groups are the active or after-training groups in exercise GSEs and are the old age groups in the aging GSEs.

Samples (n)1420810191225108
Age (y)69.6 + 9.419-7650–5750–7468.6 ± 8.470–8070.5±13.565.1 ± 7.365-76
Control group

Control groups are the sedentary or before-training groups in exercise GSEs and are the young age groups in the aging GSEs.

Samples (n)25208101610261014
Age (y)70.5+13.518–7250–5750–7424.5 ± 6.519-2521.2 ± 6.822.9 ± 4.119-28
SexMixedMixedFemaleMixedMaleMaleMixedMixedMixed
Muscle biopsyVastusVastusVastusVastusVastusVastusVastusVastusBiceps
lateralislateralislateralislateralislateralislateralislateralislateralisbrachii
Extracted moleculeTotal RNATotal RNATotal RNATotal RNATotal RNATotal RNATotal RNATotal RNATotal RNA
Organization nameBuck Institute for Research on Aging USAMayo Clinic and Foundation USAUniversity of Jyväskylä FinlandUniversity of Jyväskylä FinlandUniversity of Rochester USABoston University USABuck Institute for Research on Aging USAMayo Clinic and Foundation USAUniversity of Michigan USA

CU-DREAM comparing upregulation in exercise and downregulation in aging

Aging groupExercise group847991031690720319
GSEsGSEs (types)(Resistance)(Endurance)(Power training)(Physically active)
80P6.73 × 10–23.78 × 10–46.58 × 10–11.32 × 10–1
OR0.402.9104.14
95% CI0.15–1.101.57–5.38–0.56–30.80
1428P5.29 × 10–19.73 × 10–153.54 × 10–28.29 × 10–1
OR0.932.302.650.86
95% CI0.73–1.171.85–2.851.03–6.790.21–3.54
8479P5.07 × 10–241.34 × 10–221.20 × 10–18.31 × 10–2
OR0.162.6502.22
95% CI0.11–0.242.16–3.24–0.88–5.60
9103P4.13 × 10–22.76 × 10–125.90 × 10–15.97 × 10–1
OR0.603.170.581.70
95% CI0.36–0.992.26–4.470.08–4.200.23–12.36
38718P2.85 × 10–182.35 × 10–94.65 × 10–16.82 × 10–2
OR0.471.580.681.88
95% CI0.40–0.561.36–1.830.25–1.900.94–3.74

CU-DREAM comparing downregulation in exercise and upregulation in aging

Aging GroupExercise group847991031690720319
GSEsGSEs (types)(Resistance)(Endurance)(Power Training)(Physically active)
80P1.81 × 10–31.25 × 10–27.93 × 10–16.39 × 10–1
OR2.552.560.000.00
95% CI1.39–4.681.19–5.48––
1428P9.35 × 10–13.03 × 10–19.34 × 10–18.91 × 10–1
OR0.932.930.000.00
95% CI0.16–5.560.34–25.15––
8479P1.81 × 10–1037.43 × 10–29.05 × 10–17.52 × 10–1
OR5.651.300.890.80
95% CI4.74–6.730.97–1.740.12- 6.530.19–3.27
9103P9.14 × 10–-613.04 × 10–513.98 × 10–19.03 × 10–1
OR4.084.441.430.92
95% CI3.41–4.893.59–5.480.62-3.260.22–3.76
38718P9.22 × 10–98.59 × 10–132.32 × 10–13.09 × 10–1
OR1.502.140.001.60
95% CI1.31–1.721.73–2.64–0.64–4.01

DAVID/KEGG pathway results for endurance exercise.

Significant molecular pathwaysQ rangeNo. of GSEs in commonNo. of genesLists of genes associated with the pathways
Oxidative phosphorylation8.8 × 10–44 –1.6 × 10–25/543ATP5B, ATP5C1, ATP5E, ATP5F1, ATP5G1, ATP5G3, ATP5H, ATP5J, ATP5L, ATP5O, COX4I1, COX5A, COX5B, COX6B1, COX6C, COX7B, COX7C, COX8A, CYC1, NDUFA10, NDUFA4, NDUFA6, NDUFA8, NDUFA9, NDUFAB1, NDUFB1, NDUFB10, NDUFB2, NDUFB8, NDUFB9, NDUFC1, NDUFS1, NDUFS2, NDUFS3, NDUFS8, SDHA, SDHB, UQCR11, UQCRB, UQCRC1, UQCRC2, UQCRFS1, UQCRQ
Cardiac muscle contraction3.8 × 10–10 –2.6 × 10–53/514COX4I1, COX5A, COX5B, COX6B1, COX6C, COX7B, COX7C, COX8A, CYC1, UQCRB, UQCRC1, UQCRC2, UQCRFS1, UQCRQ
Citrate cycle (TCA cycle)

Significant in GSE 8479.

3.6 × 10–51/57SDHA, SDHB, SUCLG1, CS, PDHA1, FH, MDH1
Propanoate metabolism

Significant in GSE 8479.

8.3 × 10–31/55LDHB, ALDH7A1, ALDH1B1, SUCLG1, PCCB
Pyruvate metabolism

Significant in GSE 8479.

1.7 × 10–21/55LDHB, ALDH7A1, ALDH1B1, PDHA1, MDH1
Arginine and proline metabolism

Significant in GSE 8479.

4.1 × 10–21/55GOT2, ALDH7A1, GOT1, ALDH1B1, CKMT2

Lists of in common genes from significant CU-DREAM results comparing downregulation in resistance exercise and upregulation in aging

In common4 (n= 1)3 (n= 12)2 (n= 134
GenesCRIM1FEZ2, H3F3B, HNRNPM, LAMP1, METTL7A, NKTR, RBM5, SRRM2, TRMT112, TSC22D1, XRCC6, ZFHX3ADAMTS5, ALDH2, ALDH9A1, APBB3, ARFGAP2, ARL6IP5, ATG12, ATP1B4, ATP6V0A1, BCL6, BTG2, C1orf123, C21orf7, CALM1, CBLB, CEBPB, CELF2, CEP350, CFLAR, CLK4, COL4A3BP, CREB1, CREBBP, CXXC1, DDIT4, DHRS7, DMD, DPF2, DYNC1LI2, EFHD1, EIF1AD, ERRFI1, FAM107A, FAM8A1, FBLN1, FIGF, FILIP1, FKBP5, FOXN3, FOXO3, GGNBP2, GLG1, GLUL, GNPDA1, H1FX, HAUS2, HNRNPA1, HNRNPC, HSD17B7, HSF2, IGFBP6, IK, ING5, JDP2, KARS, KHDRBS1, KIAA0494, KLF10, KLF5, KLF9, KLHL28, LAMA2, LGR5, MBNL1, MCM7, MORC2, MYC, MYH11, NFAT5, NPHP3, NT5C2, PAM, PCM1, PDLIM5, PERP, PEX16, PHIP, PPDPF, PRDM2, PRDX6, PRKRIP1, PRNP, PTGES3, RASEF, RHEB, RNF103, RPL10A, RPL12, RPL13, RPL22, RPL23A, RPL4, RPL41, RPL7A, RPS4X, RPS6KA5, RRAD, RUNX1T1, SELM, SH3GLB1, SKAP2, SLBP, SLC7A6, SLIT2, SLPI, SMAD2, SOD3, STAG2, SUV420H1, SYNPO2, TANC1, TGFBR3, THUMPD1, TM2D3, TMEM43, TOP1, TP63, TPM3, TSR1, UACA, UBE2L3, UPF3A, USP54, VIT, WTAP, XPC, XPNPEP3, XRCC2, ZBTB16, ZMAT3, ZNF451, ZNF549, ZNF627, ZNF652

CU-DREAM comparing downregulation in exercise and downregulation in aging

Aging groupExercise group847991031690720319
GSEsGSEs (types)(Resistance)(Endurance)(Power Training)(Physically active)
80P1.47 × 10–14.72 × 10–17.60 × 10–15.84 × 10–1
OR1.441.360.000.00
95% CI0.88–2.380.58–3.17––
1428P1.81 × 10–19.97 × 10–13.44 × 10–18.72 × 10–1
OR0.891.000.001.10
95% CI0.76–1.050.73–1.37–0.34–3.54
8479P1.24 × 10–679.92 × 10–18.39 × 10–19.69 × 10–2
OR3.631.000.810.00
95% CI3.11–4.240.73–1.370.11–6.00–
9103P1.72 × 10–59.47 × 10–11.11 × 10–14.09 × 10–1
OR1.931.022.480.00
95% CI1.42–2.610.55–1.880.78–7.89–
38718P5.21 × 10–542.10 × 10–72.50 × 10–18.04 × 10–1
OR2.171.590.330.90
95% CI1.97–2.401.33–1.900.04–2.430.39–2.09

Lists of in common genes from significant CU-DREAM results comparing upregulation in endurance exercise and downregulation in aging

In common5 (n= 2)4 (n= 6)3 (n= 23)2 (n= 66)
GenesATP5C1 CYCSATP5G3, ATP5J, COX7B, CYC1, GSTK1, UQCRBBHLHE41, C14orf2, CKMT2, COQ3, COX4I1, COX7C, EIF3K, GOT2, MRPS12, NDUFA4, NDUFB1, NDUFB2, NDUFB8, NEDD1, PDE4A, PPIF, PRDX2, SIRT5, SLC16A1, SLC38A1, ST8SIA5, TPI1, UQCRFS1ACSL6, ALDH1B1, ALDH7A1, ATP5E, ATP5F1, ATP5G1, ATP5L, ATP5O, BCAP29, BOLA3, C1orf151, C21orf33, C2orf88, CALU, CHCHD10, COX5A, COX5B, CS, DECR1, DPH5, DTNA, DUS4L, FAM162A, FH, FLJ11292, FRMD3, FYN, GNPTAB, GOSR2, GOT1, GPCPD1, GULP1, MIPEP, MRPL15, MRPL35, MRPL41, NDUFA6, NDUFA9, NDUFAB1, NDUFC1, NDUFS3, NDUFS8, NUDT6, OXNAD1, OXSM, PARVB, PDHA1, PHC3, POU6F1, PTCD3, PTPRO, RUNX2, SH3KBP1, SLC25A11, SLC25A4, ST6GALNAC2, SUCLG1, TMEM164, TNFAIP2, TOR3A, TUB, UQCRC1, UQCRC2, UQCRQ, WDR45, ZNF252

Molecular functions and phenotypes of genes significant in endurance exercise from the Kyoto Encyclopedia of Genes and Genomes oxidative phosphorylation pathway

GeneNumber of GSEs in commonP rangeMolecular functionMolecular and cellular phenotypes
ATP5C15/56.80 × 10–5 to 8.86 × 10–3ATP synthase γ-subunitCatalyzes AT P synthesis, mainly expressed in the heart
ATP5G34/54.12 × 10–7 to 2.06 × 10–3ATP synthase lipid-binding Catalyzes ATP synthesis protein
ATP5J4/56.58 × 10–5 to 3.57 × 10–3ATP synthase-coupling factorCatalyzes AT P synthesis
COX7B4/58.81 × 10–5 to 6.36 × 10–3Cytochrome C oxidase subunitTerminal oxidase in the mitochondrial electron transport
Accepts electrons from the Rieske
CYC14/51.34 × 10–5 to 6.77 × 10–3Cytochrome Cprotein and transfers electrons to cytochrome c in the mitochondrial
respiratory chain
UQCRB4/59.80 × 10–6 to 4.15 × 10–3Ubiquinol-Cytochrome C reductase complex subunitRedox-linked proton pumping
COX4I13/51.69 × 10–4 to 9.69 × 10–4Cytochrome C oxidase subunitCatalyzes the electron transfer from reduced cytochrome c to oxygen
COX7C3/52.20 × 10–4 to 9.60 × 10–3Cytochrome C oxidase subunitCatalyzes the electron transfer from reduced cytochrome c to oxygen
NDUFA 43/57.89 × 10–4 to 8.57 × 10–3α-Subcomplex subunitTransfer of electrons from NADH to the respiratory chain
NDUFB13/54.95 × 10–5 to 5.58 × 10–3β-Subcomplex subunitTransfer of electrons from NADH to the respiratory chain
NDUFB23/54.35 × 10–3 to 6.58 × 10–3β-Subcomplex SubunitTransfer of electrons from NADH to the respiratory chain
NDUFB83/54.03 × 10–7 to 4.14 × 10–3β-Subcomplex SubunitTransfer of electrons from NADH to the respiratory chain
UQCRFS13/56.28 × 10–6 to 2.61 × 10–3Ubiquinol-Cytochrome C reductase complex subunitGenerates an electrochemical potential coupled to ATP synthesis

Molecular functions and phenotypes of significant remaining genes in endurance exercise

GeneNumber of GSEs in commonP rangeMolecular functionMolecular and cellular phenotypes
CYCS5/56.96 × 10–5 to 4.85 × 10–3Cytochrome CElectron carrier protein, important apoptotic role
GSTK14/53.22 × 10–5 to 7.78 × 10–3Glutathione S-transferase subunitCellular detoxification
BHLHE413/51.34 × 10–6 to 9.60 × 10–3Helix-loop-helix proteinTranscriptional repressor
C14orf23/57.06 × 10–5 to 4.83 × 10–3Mitochondrial proteolipidChromosome 14 open reading frame Reversibly catalyzes the transfer of
CKMT23/57.66 × 10–9 to 5.91 × 10–3Mitochondrial creatine kinasephosphate between ATP and phosphagens
COQ33/57.39 × 10–5 to 7.27 × 10–3COQ3 methyltransferaseCoenzyme Q biosynthesis Prevents premature joining of the 40S
EIF3K3/51.34 × 10–4 to 5.21 × 10–3Translation initiation factorand 60S ribosomal subunits prior to initiation
GOT23/55.26 × 10–6 to 6.07 × 10–3Fatty acid-binding proteinAmino acid metabolism, facilitates cellular uptake of long-chain free fatty acids Key component of the small ribosomal subunit
MRPS123/55.51 × 10–4 to 3.48 × 10–3Mitochondrial ribosomal protein
NEDD13/52.64 × 10–4 to 3.45 × 10–3Neural precursor cell proteinMitosis progression, promotes the nucleation of microtubules from the spindle
PDE4A3/52.16 × 10–4 to 2.53 × 10–3Phosphodiesterase isozymeRegulating the cellular concentration of cAMP
PPIF3/53.69 × 10–5 to 6.88 × 10–3Mitochondrial cyclophilinAntiapoptotic activity
PRDX23/54.61 × 10–4 to 9.86 × 10–3Thiol-specific antioxidantEliminating peroxides generated during metabolism
SIRT53/52.03 × 10–4 to 4.98 × 10–3Regulatory proteinRegulation of transcription and apoptosis
SLC16A13/56.38 × 10–5 to 9.09 × 10–3Solute carrierCatalyzes the movement of monocarboxylates across the plasma membrane
SLC38A13/53.49 × 10–5 to 9.75 × 10–4Solute carrierMediates cotransport of glutamine and sodium ions
ST8SIA53/51.04 × 10–5 to 1.97 × 10–3SialyltransferaseSynthesis of gangliosides
TPI13/53.33 × 10–5 to 9.54 × 10–3Triosephosphate isomeraseCatalyzes the isomerization of G3P and DHAP in glycolysis and gluconeogenesis
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