Cited by 475Muscle metabolism and nutritionMuscle Physiology and DisordersMetabolism, Diabetes, and Cancer

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Selective activation of AMPK‐PGC‐1α or PKB‐TSC2‐mTOR signaling can explain specific adaptive responses to endurance or resistance training‐like electrical muscle stimulation

Atherton, Philip J., Babraj, John A., Smith, Kenneth, Singh, Jaipaul, Rennie, Michael J., Wackerhage, Henning·2005·The FASEB Journal

DOI 10.1096/fj.04-2179fje

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Abstract

Endurance training induces a partial fast-to-slow muscle phenotype transformation and mitochondrial biogenesis but no growth. In contrast, resistance training mainly stimulates muscle protein synthesis resulting in hypertrophy. The aim of this study was to identify signaling events that may mediate the specific adaptations to these types of exercise. Isolated rat muscles were electrically stimulated with either high frequency (HFS; 6x10 repetitions of 3 s-bursts at 100 Hz to mimic resistance training) or low frequency (LFS; 3 h at 10 Hz to mimic endurance training). HFS significantly increased myofibrillar and sarcoplasmic protein synthesis 3 h after stimulation 5.3- and 2.7-fold, respectively. LFS had no significant effect on protein synthesis 3 h after stimulation but increased UCP3 mRNA 11.7-fold, whereas HFS had no significant effect on UCP3 mRNA. Only LFS increased AMPK phosphorylation significantly at Thr172 by approximately 2-fold and increased PGC-1alpha protein to 1.3 times of control. LFS had no effect on PKB phosphorylation but reduced TSC2 phosphorylation at Thr1462 and deactivated translational regulators. In contrast, HFS acutely increased phosphorylation of PKB at Ser473 5.3-fold and the phosphorylation of TSC2, mTOR, GSK-3beta at PKB-sensitive sites. HFS also caused a prolonged activation of the translational regulators p70 S6k, 4E-BP1, eIF-2B, and eEF2. These data suggest that a specific signaling response to LFS is a specific activation of the AMPK-PGC-1alpha signaling pathway which may explain some endurance training adaptations. HFS selectively activates the PKB-TSC2-mTOR cascade causing a prolonged activation of translational regulators, which is consistent with increased protein synthesis and muscle growth. We term this behavior the "AMPK-PKB switch." We hypothesize that the AMPK-PKB switch is a mechanism that partially mediates specific adaptations to endurance and resistance training, respectively.

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“However, Low-Frequency Electrical Stimulation (LFES, simulating low-force contractions) and High-Frequency Electrical Stimulation (HFES, simulating high-force contractions) allow the effect of load on RE adaptations to be analysed [34,35].”
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The Role of Mammalian Target of Rapamycin (mTOR) and Adenosine Monophosphate-Activated Protein Kinase (AMPK) Signaling in Skeletal Muscle Hypertrophy: A Literature Review With Implications for Health and Disease
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Role of Mammalian Target of Rapamycin in Muscle Growth
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“…to control levels at 3 h. Metabolically demanding contractile work is thought to induce a transient AMPK- and/or Ca2+/calmodulin-mediated suppression of myofibremTORC1 and eEF2 elongation activity (Atherton et al., 2005; Dreyer et al., 2006; Rose, Alsted, et al., 2009; Rose, Bisiani, et al., 2009).”
Background
Regulating eEF2 and eEF2K in skeletal muscle by exercise
Salimi, K., Alvandi, M., Pirouz, M. S., Rakhshan, K., & Howatson, G. (2023) · Archives of Physiology and Biochemistry · doi:10.1080/13813455.2023.2164898 · Cited by 3
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Six weeks of high-load resistance and low-load blood flow restricted training increase Na/K-ATPase sub-units α2 and β1 equally, but does not alter ClC-1 abundance in untrained human skeletal muscle
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“While endurance exercise causes minor and gradual ATP depletion, it is also characterized by lower frequency of AP firing rate compared to HLRE (Atherton et al. 2005).”
Result
Skeletal muscle signaling response to concurrent endurance and resistance exercise
Makanae, Y., Ogasawara, R., & Fujita, S. (2015) · The Journal of Physical Fitness and Sports Medicine · doi:10.7600/jpfsm.4.217 · Cited by 3
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“…pathways in endurance exercise, swim training involves prolonged and continuous muscle contractions inaerobicconditionsandrobustlyactivatestheAMPKandperoxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 α ) signalling axes (Atherton et al., 2005; Baar et al., 2002).”
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“AMPK was activated at 3 hrs post LFS, whilst HFS failed to increase AMPK activity (Atherton et al., 2005).”
Background
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Wackerhage, H., & Atherton, P. J. (2006) · Elsevier eBooks · doi:10.1016/b978-0-443-10077-2.50009-2 · Cited by 2
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Authors: Atherton, P. J., Babraj, J. A., Smith, K., Singh, J., Rennie, M. J., & Wackerhage, H.
Affiliations: University of Nottingham (GB)
University of Dundee (GB)
University of Lancashire (GB)
ORCID: Atherton, Philip J.
Babraj, John A.
Smith, Kenneth
Singh, Jaipaul
Rennie, Michael J.
Wackerhage, Henning
Venue: The FASEB Journal
Publisher: Wiley
Published: 2005-02-16
Volume: 19
Issue: 7
Pages: 1-23
ISSN: 0892-6638 (ISSN-L)
1530-6860
DOI: 10.1096/fj.04-2179fje
OpenAlex: W2115928938
Cited by: 475
References: 62
Citations by year: 2026: 9 · 2025: 11 · 2024: 10 · 2023: 21 · 2022: 15 · 2021: 15 · 2020: 18 · 2019: 25 · 2018: 35 · 2017: 16 · 2016: 22 · 2015: 20 · 2014: 30 · 2013: 33 · 2012: 23
FWCI: 12.47
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: The FASEB Journal (publishedVersion)
PubMed (publishedVersion)
CLOK (University of Central Lancashire) (submittedVersion)
Funders: National Institutes of Health (AR 49869)
Biotechnology and Biological Sciences Research Council
Diabetes UK
Tenovus
University of Central Lancashire
University of Dundee
Topics: Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: AMPK/PGC-1α signaling, neuromuscular electrical stimulation, high-frequency stimulation, low-frequency stimulation, endurance training adaptation, resistance training adaptation, muscle protein synthesis, muscle hypertrophy, mitochondrial biogenesis, UCP3, translational regulation, p70S6K, 4E-BP1
MeSH terms: Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Tuberous Sclerosis Complex 2 Protein, Adaptation, Physiological, Adenylate Kinase, Animals, Electric Stimulation, Enzyme Activation, Physical Exertion, Male, Muscle Contraction, Muscle Proteins, Myofibrils, Phosphorylation, Physical Conditioning, Animal, Physical Endurance, Protein Kinases, Sarcoplasmic Reticulum, Transcription Factors, Signal Transduction, RNA-Binding Proteins, Rats, Wistar, Muscle, Skeletal, Mitogen-Activated Protein Kinases, Tumor Suppressor Proteins, Proto-Oncogene Proteins c-akt, Rats, TOR Serine-Threonine Kinases

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Selective activation of AMPK‐PGC‐1α or PKB‐TSC2‐mTOR signaling can explain specific adaptive responses to endurance or resistance training‐like electrical muscle stimulation

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