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Resistance exercise induced S6K1 kinase activity is not inhibited in human skeletal muscle despite prior activation of AMPK by high intensity interval cycling.
Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Eva Blomstrand's research group.ORCID iD: 0000-0003-1942-2919
Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Eva Blomstrand's research group.ORCID iD: 0000-0003-3747-0148
Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Björn Ekblom's and Mats Börjesson's research group.ORCID iD: 0000-0002-4030-5437
Show others and affiliations
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.

Place, publisher, year, edition, pages
2015. Vol. 308, no 6, E470-E481 p.
National Category
Medical and Health Sciences
Research subject
Medicine/Technology
Identifiers
URN: urn:nbn:se:gih:diva-3322DOI: 10.1152/ajpendo.00486.2014OAI: oai:DiVA.org:gih-3322DiVA: diva2:720011
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
In thesis
1. Regulation of protein synthesis in human skeletal muscle: separate and combined effects of exercise and amino acids
Open this publication in new window or tab >>Regulation of protein synthesis in human skeletal muscle: separate and combined effects of exercise and amino acids
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:nbn:se:gih:diva-3323 (URN)978-91-7549-513-2 (ISBN)
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
2. Effects of exercise and amino acid intake on mechanisms regulating protein synthesis and breakdown in human muscle
Open this publication in new window or tab >>Effects of exercise and amino acid intake on mechanisms regulating protein synthesis and breakdown in human muscle
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Skeletal muscle adapts differently to specific modes of exercise, where resistance training results in muscle growth and endurance training induces mitochondrial biogenesis. These are results of molecular events that occur after each exercise session, increasing the expression of specific genes and the rate of both synthesis and breakdown of protein. The rate of protein synthesis is controlled by the mTORC1 signaling pathway, which is potently stimulated by resistance exercise and amino acid, and their combined effect is needed for muscle growth. The essential amino acids (EAA) are responsible for the stimulation of protein synthesis and here leucine has been attributed specific attention, but its particular role among the EAA, and the involvement of the other branched-chain amino acids (BCAA) is unclear. Endurance exercise activates the protein AMPK which, in animal models, has been shown to inhibit mTORC1 signaling and protein synthesis.  Suggesting that concurrent endurance and resistance exercise could restrain muscle growth, but it is unknown if this mechanism is relevant in exercising human muscle. Little is known about the regulation of protein breakdown and although much attention has been given the proteins MuRF-1 and MAFbx which target proteins for degradation, their role requires further investigation. The aim of thesis was to address the mentioned uncertainties by examining how different modes of exercise and amino acids affect mTORC1 signaling, protein synthesis and markers of protein breakdown in human muscle.

In study I, the influence of high intensity endurance exercise on subsequent resistance exercised induced mTORC1 signaling was examined. Despite robust activation of AMPK by the endurance exercise there was no inhibition of mTORC1 signaling or protein synthesis during recovery from resistance exercise. Study II utilized a similar set up, but with the difference that resistance exercise was performed with the triceps. The cycling exercise reduced the resistance exercise stimulated mTORC1 signaling immediately after the exercise, but during the recovery period mTORC1 signaling and protein synthesis was similar between trials. Concurrent exercise induced the mRNA expression of MuRF-1 and that of PGC-1α, the master regulator of mitochondrial biogenesis, in both studies, despite that the exercise modes in study II were separated between legs and arms. In study III, the effect of an EAA supplement with or without leucine, in the stimulation of mTORC1 signaling in connection with resistance exercise was examined. Intake of EAA robustly stimulated mTORC1 signaling after exercise, but this was only minor when leucine was excluded from the supplement. In study IV, subjects were supplied with leucine, BCAA, EAA or placebo in a randomized fashion during four sessions of resistance exercise. Leucine alone stimulated mTORC1 signaling after the exercise, but both the amplitude and extent of stimulation was substantially greater with EAA, an effect that was largely mediated by the BCAA as a group.

In conclusion, endurance exercise prior to resistance exercise using the leg or arm muscles does not affect mTORC1 signaling or protein synthesis during the three hour recovery period from exercise, supporting compatibility between resistance- and endurance exercise induced signaling. Concurrent exercise increases the expression of the proteolytic marker MuRF-1 compared to resistance exercise only, which could indicate both and increased demand of cellular adaptive remodeling or a more direct detrimental proteolytic effect. Leucine is crucial among the EAA in the stimulation of mTORC1 signaling after exercise, its effect is however potentiated by intake of the remaining EAA. As a supplement a mixture of EAA must be regarded preferable, although the effect is largely mediated by the BCAA as a group.  

 

Place, publisher, year, edition, pages
Stockholm: Gymnastik- och idrottshögskolan, 2016. 109 p.
Series
Avhandlingsserie för Gymnastik- och idrottshögskolan, 07
Keyword
Resistance exercise, concurrent exericse, leucine, BCAA, mTORC1 signaling, protein synthesis, MuRF-1, PGC-1alpha
National Category
Sport and Fitness Sciences Cell and Molecular Biology
Research subject
Medicine/Technology
Identifiers
urn:nbn:se:gih:diva-4371 (URN)978-91-980862-6-3 (ISBN)
Public defence
2016-04-01, Aulan, Lidingövägen 1, Stockholm, 09:00 (English)
Opponent
Supervisors
Funder
Swedish National Centre for Research in Sports
Available from: 2016-03-01 Created: 2016-03-01 Last updated: 2016-03-08Bibliographically approved

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