Downregulation of Akt/Mammalian Target of Rapamycin Pathway in Skeletal Muscle Is Associated with Increased REDD1 Expression in Response to Chronic Hypoxia
Abstract
Although it is well established that chronic hypoxia leads to an inexorable loss of skeletal muscle mass in healthy subjects, the underlying molecular mechanisms involved in this process are currently unknown. Skeletal muscle atrophy is also an important systemic consequence of chronic obstructive pulmonary disease (COPD), but the role of hypoxemia in this regulation is still debated. Our general aim was to determine the molecular mechanisms involved in the regulation of skeletal muscle mass after exposure to chronic hypoxia and to test the biological relevance of our findings into the clinical context of COPD. Expression of positive and negative regulators of skeletal muscle mass were explored 1) in the soleus muscle of rats exposed to severe hypoxia (6,300 m) for 3 wk and 2) in vastus lateralis muscle of nonhypoxemic and hypoxemic COPD patients. In rodents, we observed a marked inhibition of the mammalian target of rapamycin (mTOR) pathway together with a strong increase in regulated in development and DNA damage response 1 (REDD1) expression and in its association with 14-3-3, a mechanism known to downregulate the mTOR pathway. Importantly, REDD1 overexpression in vivo was sufficient to cause skeletal muscle fiber atrophy in normoxia. Finally, the comparative analysis of skeletal muscle in hypoxemic vs. nonhypoxemic COPD patients confirms that hypoxia causes an inhibition of the mTOR signaling pathway. We thus identify REDD1 as a negative regulator of skeletal muscle mass…
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In experimental models, hypoxia clearly induces muscle wasting, as evidenced by reports showing muscle atrophy even after only a few days of hypoxia exposure.
“In experimental models, hypoxia clearly induces muscle wasting, as evidenced by several reports showing muscle atrophy even after only few days of hypoxia exposure [67,68].”
From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [67]
In the study of Favier and colleagues, hypoxia was followed by a downregulation of the anabolic pathway's mTOR.
“In the study of Favier and colleagues, hypoxia was followed by a downregulation of the anabolic pathway’s mechanistic target of rapamycin (mTOR) [67]”
From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [67]
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Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression
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Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting
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“In the study of Favier and colleagues, hypoxia was followed by a downregulation of the anabolic pathway’s mechanistic target of rapamycin (mTOR) [67] (see Section 9.”
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Horwath, O., Nordström, F., von Walden, F., Apró, W., & Moberg, M. (2023) · The FASEB Journal · doi:10.1096/fj.202202065rr · Cited by 6 · see citing works
- Authors
- Favier, F. B., Costes, F., Defour, A., Bonnefoy, R., Lefai, E., Baugé, S., Peinnequin, A., Benoit, H., & Freyssenet, D.
- Affiliations
- Université de Montpellier (FR)
- Université de Lyon (FR)
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM U870 Régulations Métaboliques Nutrition et Diabètes, Oullins, France;
- Service de Santé des Armées (FR)
- Corresponding author
- Benoit, Henri
- Venue
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Publisher
- American Physiological Society
- Published
- 2010-06
- Volume
- 298
- Issue
- 6
- Pages
- R1659-R1666
- ISSN
- 0363-6119 (ISSN-L)
- 1522-1490
- OpenAlex
- W2031308904
- Cited by
- 127
- References
- 6
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 4 · 2023: 9 · 2022: 3 · 2021: 7 · 2020: 3 · 2019: 11 · 2018: 8 · 2017: 9 · 2016: 8 · 2015: 9 · 2014: 14 · 2013: 13 · 2012: 7
- FWCI
- 4.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › High Altitude and Hypoxia
- Keywords
- chronic hypoxia, skeletal muscle atrophy, mTOR signaling, REDD1, chronic obstructive pulmonary disease, hypoxemia, Akt signaling, muscle fiber atrophy, soleus muscle, vastus lateralis
- MeSH terms
- Animals, Hypoxia, Atrophy, Humans, Male, Mammals, Muscular Atrophy, Signal Transduction, Down-Regulation, Rats, Wistar, Muscle, Skeletal, Sirolimus, Pulmonary Disease, Chronic Obstructive, Proto-Oncogene Proteins c-akt, Rats
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