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Regulation of protein synthesis in human skeletal muscle: separate and combined effects of exercise and amino acids
Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Eva Blomstrand's research group. Karolinska Institutet, Inst för klinisk vetenskap, intervention och teknik / Dept of Clinical Science, Intervention and Technology.ORCID iD: 0000-0003-1942-2919
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Skeletal muscle is a highly plastic tissue which has the ability to adapt to various forms of external stimuli such as diverse modes of contractile activity. Thus, performance of endurance exercise over several of weeks results in increased oxidative capacity. In contrast, prolonged performance of resistance exercise ultimately results in increased muscle mass. These adaptations are brought about by transient alterations in gene expression and mRNA translation which result in altered protein turnover, i.e. the balance between protein synthesis and protein breakdown. Protein synthesis is the major determinant of muscle growth, which at the molecular level, is regulated by the mTORC1 pathway. This pathway is potently activated by resistance exercise and amino acids, but the stimulatory role of individual amino acids in human skeletal muscle is unclear. Muscle adaptations in response to endurance exercise are largely dependent on the PGC-1 α pathway, which regulates mitochondrial biogenesis. Given the different training adaptations after resistance and endurance exercise, it has been suggested that these exercise modalities may be incompatible when combined. Such potential interference could be exerted at the molecular level between the pathways responsible for each adaptive response. AMPK, an enzyme usually activated by endurance exercise and, when pharmacologically activated in cell culture and rodent models, has been shown to inhibit mTORC1 and protein synthesis. However, it is not known if activation of AMPK by endurance exercise inhibits resistance exercise induced signaling through the mTORC1 pathway in human skeletal muscle.

Thus, the main objective of this thesis was to examine the molecular mechanisms regulating protein synthesis in response to amino acids and various modes of exercise in human skeletal muscle.

In study I, the role of BCAAs in stimulating the mTORC1 pathway was examined in both resting and exercising muscle. BCAA increased mTORC1 activity, as assessed by S6K1 phosphorylation, in both resting and exercising muscle, but more so when exercise and BCAA were combined. In study II, the effect of leucine was compared to that of essential amino acids with or without leucine. It was found that when leucine was combined with the remaining essential amino acids, S6K1 phosphorylation was more pronounced than when leucine was provided alone. Furthermore, when leucine was removed from the essential amino acids, the effect was equal to that of placebo. In study III, the impact of endurance exercise on resistance exercise induced mTORC1 signaling was examined. When performed after resistance exercise, endurance exercise did not inhibit S6K1 phosphorylation compared to when single mode resistance exercise was performed. In study IV, performance of high intensity endurance exercise prior to resistance exercise did not inhibit S6K1 phosphorylation compared to single mode resistance exercise, despite prior activation of AMPK.

In conclusion, amino acids and resistance exercise activate mTORC1 signaling, as assessed by S6K1 phosphorylation, in a synergistic manner. Leucine is crucial in mediating the amino acid response, however, additional amino acids appear to be required to induce a maximal response downstream of mTORC1. Activation of the mTORC1 pathway in response to heavy resistance exercise is robust and this activation does not appear to be inhibited by prior or by subsequent endurance exercise. As such, these results do not lend support to the existence of molecular interference when resistance and endurance exercise are combined acutely.

Place, publisher, year, edition, pages
Karolinska Institutet , 2014.
National Category
Medical and Health Sciences
Research subject
Medicine/Technology
Identifiers
URN: urn:nbn:se:gih:diva-3323ISBN: 978-91-7549-513-2 (print)OAI: oai:DiVA.org:gih-3323DiVA: diva2:720153
Public defence
2014-06-13, Aulan, Gymnastik- och idrottshögskolan, Lidingövägen 1, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2014-05-28 Created: 2014-05-28 Last updated: 2016-06-20Bibliographically approved
List of papers
1. Influence of supplementation with branched-chain amino acids in combination with resistance exercise on p70S6 kinase phosphorylation in resting and exercising human skeletal muscle.
Open this publication in new window or tab >>Influence of supplementation with branched-chain amino acids in combination with resistance exercise on p70S6 kinase phosphorylation in resting and exercising human skeletal muscle.
2010 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 200, no 3, 237-48 p.Article in journal (Refereed) Published
Abstract [en]

AIM: Skeletal muscle growth is thought to be regulated by the mammalian target of rapamycin (mTOR) pathway, which can be activated by resistance exercise and branched-chain amino acids (BCAA). The major aim of the present study was to distinguish between the influence of resistance exercise and BCAA on key enzymes considered to be involved in the regulation of protein synthesis, including p70(S6) kinase (p70(S6k)). METHODS: Nine healthy subjects (four men and five women) performed unilateral resistance exercise on two occasions separated by 1 month. Subjects were randomly supplied either a mixture of BCAA or flavoured water. Muscle biopsies were taken from both resting and exercising muscle before, after and 1 h after exercise. RESULTS: Phosphorylation of Akt was unaltered by either resistance exercise and/or BCAA supplementation whereas mTOR phosphorylation was enhanced (P<0.05) to a similar extent in both exercising and resting muscle following exercise in the absence (70-90%) and presence of BCAA supplementation (80-130%). Phosphorylation of p70(S6k) was unaffected by resistance exercise alone; however, BCAA intake increased (P<0.05) this phosphorylation in both legs following exercise. In resting muscle, a 5- and 16-fold increase in p70(S6k) was observed immediately after and 1 h after exercise, respectively, as compared to 11- and 30-fold increases in the exercising muscle. Phosphorylation of eukaryotic elongation factor 2 was attenuated 1 h after exercise (P<0.05) in both resting (10-40%) and exercising muscle (30-50%) under both conditions. CONCLUSION: The present findings indicate that resistance exercise and BCAA exert both separate and combined effects on the p70(S6k) phosphorylation in an Akt-independent manner.

National Category
Physiology
Research subject
Medicine/Technology
Identifiers
urn:nbn:se:gih:diva-1480 (URN)10.1111/j.1748-1708.2010.02151.x (DOI)20528801 (PubMedID)
Available from: 2010-11-10 Created: 2010-11-10 Last updated: 2017-12-12Bibliographically approved
2. Leucine does not affect mTORC1 assembly but is required for maximal S6K1 activity in human skeletal muscle following resistance exercise
Open this publication in new window or tab >>Leucine does not affect mTORC1 assembly but is required for maximal S6K1 activity in human skeletal muscle following resistance exercise
Show others...
(Swedish)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Medicine/Technology
Identifiers
urn:nbn:se:gih:diva-3321 (URN)
Note

At the time of William Apró's dissertation the publication was a manuscript.

Available from: 2014-05-27 Created: 2014-05-27 Last updated: 2017-03-31Bibliographically approved
3. Resistance exercise induced mTORC1 signaling is not impaired by subsequent endurance exercise in human skeletal muscle.
Open this publication in new window or tab >>Resistance exercise induced mTORC1 signaling is not impaired by subsequent endurance exercise in human skeletal muscle.
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2013 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 305, no 1, E22-32 p.Article in journal (Refereed) Published
Abstract [en]

The current dogma is that the muscle adaptation to resistance exercise is blunted when combined with endurance exercise. The suggested mechanism (based on rodent experiments) is that activation of adenosine monophosphate-activated protein kinase (AMPK) during endurance exercise impairs muscle growth through inhibition of the mechanistic target of rapamycin complex 1 (mTORC1). The purpose of this study was to investigate potential interference of endurance training on the signaling pathway of resistance training [mTORC1 phosphorylation of ribosomal protein S6 kinase 1 (S6K1)] in human muscle. Ten healthy and moderately trained male subjects performed on two separate occasions either acute high-intensity and high-volume resistance exercise (leg press, R) or R followed by 30 min of cycling (RE). Muscle biopsies were collected before and 1 and 3 h post resistance exercise. Phosphorylation of mTOR (Ser(2448)) increased 2-fold (P < 0.05) and that of S6K1 (Thr(389)) 14-fold (P < 0.05), with no difference between R and RE. Phosphorylation of eukaryotic elongation factor 2 (eEF2, Thr(56)) was reduced ∼70% during recovery in both trials (P < 0.05). An interesting finding was that phosphorylation of AMPK (Thr(172)) and acetyl-CoA carboxylase (ACC, Ser(79)) decreased ∼30% and ∼50%, respectively, 3 h postexercise (P < 0.05). Proliferator-activated receptor-γ coactivator-1 (PGC-1α) mRNA increased more after RE (6.5-fold) than after R (4-fold) (RE vs. R: P < 0.01) and was the only gene expressed differently between trials. These data show that the signaling of muscle growth through the mTORC1-S6K1 axis after heavy resistance exercise is not inhibited by subsequent endurance exercise. It is also suggested that prior activation of mTORC1 signaling may repress subsequent phosphorylation of AMPK.

National Category
Physiology
Research subject
Medicine/Technology
Identifiers
urn:nbn:se:gih:diva-2851 (URN)10.1152/ajpendo.00091.2013 (DOI)23632629 (PubMedID)
Funder
Swedish National Centre for Research in Sports, P2011-0026
Available from: 2013-08-05 Created: 2013-08-05 Last updated: 2017-12-06Bibliographically approved
4. Resistance exercise induced S6K1 kinase activity is not inhibited in human skeletal muscle despite prior activation of AMPK by high intensity interval cycling.
Open this publication in new window or tab >>Resistance exercise induced S6K1 kinase activity is not inhibited in human skeletal muscle despite prior activation of AMPK by high intensity interval cycling.
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2015 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 308, no 6, E470-E481 p.Article in journal (Refereed) Published
Abstract [en]

Combining endurance and strength training in the same session has been reported to reduce the anabolic response to the latter form of exercise. The underlying mechanism, based primarily on results from rodent muscle, is proposed to involve AMPK-dependent inhibition of mTORC1 signaling. This hypothesis was tested in eight trained male subjects who in a randomized order performed either resistance exercise only (R) or interval cycling followed by resistance exercise (ER). Biopsies taken from the vastus lateralis before and after endurance exercise and repeatedly after resistance exercise were assessed for glycogen content, kinase activity, protein phosphorylation and gene expression. Mixed muscle fractional synthetic rate was measured at rest and during 3h of recovery using the stable isotope technique. In ER, AMPK activity was elevated immediately after both endurance and resistance exercise (~90%, P<0.05) but was unchanged in R. Thr389 phosphorylation of S6K1 was increased several-fold immediately after exercise (P<0.05) in both trials and increased further throughout recovery. After 90 and 180 min recovery, S6K1 activity was elevated (~55% and ~110%, respectively, P<0.05) and eEF2 phosphorylation was reduced (~55%, P<0.05) with no difference between trials. In contrast, markers for protein catabolism were differently influenced by the two modes of exercise; ER induced a significant increase in gene and protein expression of MuRF1 (P<0.05), which was not observed following R exercise only. In conclusion, cycling-induced elevation in AMPK activity does not inhibit mTORC1 signaling after subsequent resistance exercise, but may instead interfere with the hypertrophic response by influencing key components in protein breakdown.

National Category
Medical and Health Sciences
Research subject
Medicine/Technology
Identifiers
urn:nbn:se:gih:diva-3322 (URN)10.1152/ajpendo.00486.2014 (DOI)
Note

At the time of William Apró's dissertation the publication was a manuscript.

Available from: 2014-05-27 Created: 2014-05-27 Last updated: 2017-12-05Bibliographically approved

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