Abstract
In this study, the coordinated activation of ubiquitin-proteasome pathway (UPP), autophagy-lysosomal pathway (ALP), and mitochondrial remodeling including mitophagy was assessed by measuring protein markers during ultra-endurance running exercise in human skeletal muscle. Eleven male, experienced ultra-endurance athletes ran for 24 h on a treadmill. Muscle biopsy samples were taken from the vastus lateralis muscle 2 h before starting and immediately after finishing exercise. Athletes ran 149.8 ± 16.3 km with an effective running time of 18 h 42 min ( ± 41 min). The phosphorylation state of Akt (-74 ± 5%; P < 0.001), FOXO3a (-49 ± 9%; P < 0.001), mTOR Ser2448 (-32 ± 14%; P = 0.028), and 4E-BP1 (-34 ± 7%; P < 0.001) was decreased, whereas AMPK phosphorylation state increased by 247 ± 170% (P = 0.042). Proteasome β2 subunit activity increased by 95 ± 44% (P = 0.028), whereas the activities associated with the β1 and β5 subunits remained unchanged. MuRF1 protein level increased by 55 ± 26% (P = 0.034), whereas MAFbx protein and ubiquitin-conjugated protein levels did not change. LC3bII increased by 554 ± 256% (P = 0.005), and the form of ATG12 conjugated to ATG5 increased by 36 ± 17% (P = 0.042). The mitochondrial fission marker phospho-DRP1 increased by 110 ± 47% (P = 0.003), whereas the fusion marker Mfn1 and the mitophagy markers Parkin and PINK1 remained unchanged. These results fit well with a coordinated regulation of ALP and UPP triggered by FOXO3 and AMPK during ultra-endurance exercise.
Trial registration:
ClinicalTrials.gov NCT00428779.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / metabolism
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Adaptor Proteins, Signal Transducing / metabolism
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Adult
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Autophagy*
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Autophagy-Related Protein 12
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Autophagy-Related Protein 5
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Biopsy
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Blood Glucose / metabolism
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Cell Cycle Proteins
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Dynamins
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Energy Intake
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Energy Metabolism
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Forkhead Box Protein O3
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Forkhead Transcription Factors / metabolism
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GTP Phosphohydrolases / metabolism
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Humans
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Insulin / blood
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Male
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Microtubule-Associated Proteins / metabolism
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Middle Aged
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Mitochondria, Muscle / enzymology
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Mitochondria, Muscle / pathology
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Mitochondrial Membrane Transport Proteins / metabolism
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Mitochondrial Proteins / metabolism
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Muscle Proteins / metabolism
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Phosphoproteins / metabolism
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Phosphorylation
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Physical Endurance*
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Proteasome Endopeptidase Complex / metabolism*
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Protein Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Quadriceps Muscle / enzymology*
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Quadriceps Muscle / pathology*
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Running
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SKP Cullin F-Box Protein Ligases / metabolism
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Serine
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Signal Transduction
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Small Ubiquitin-Related Modifier Proteins / metabolism
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TOR Serine-Threonine Kinases / metabolism
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Time Factors
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Tripartite Motif Proteins
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Ubiquitin / metabolism*
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Ubiquitin-Protein Ligases / metabolism
Substances
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ATG12 protein, human
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ATG5 protein, human
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Adaptor Proteins, Signal Transducing
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Autophagy-Related Protein 12
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Autophagy-Related Protein 5
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Blood Glucose
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Cell Cycle Proteins
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EIF4EBP1 protein, human
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FOXO3 protein, human
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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Insulin
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MAP1LC3B protein, human
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Microtubule-Associated Proteins
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Proteins
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Muscle Proteins
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Phosphoproteins
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Small Ubiquitin-Related Modifier Proteins
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Tripartite Motif Proteins
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Ubiquitin
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Serine
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FBXO32 protein, human
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SKP Cullin F-Box Protein Ligases
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TRIM63 protein, human
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Ubiquitin-Protein Ligases
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parkin protein
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Protein Kinases
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MTOR protein, human
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PTEN-induced putative kinase
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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AMP-Activated Protein Kinases
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PSMB2 protein, human
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PSMB5 protein, human
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Proteasome Endopeptidase Complex
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ATP dependent 26S protease
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GTP Phosphohydrolases
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Mfn1 protein, human
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DNM1L protein, human
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Dynamins
Associated data
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ClinicalTrials.gov/NCT00428779