Akt deficiency attenuates muscle size and function but not the response to ActRIIB inhibition
Open accessAbstract
BACKGROUND: Akt is a critical mediator of developmental skeletal muscle growth. Treatment with a soluble ActRIIB fusion protein (ActRIIB-mFc) increases skeletal muscle mass and strength by inhibiting myostatin and related peptides. Recent in vitro studies have suggested that Akt signaling is necessary for the ability of ActRIIB inhibition to induce muscle hypertrophy. Thus, we hypothesized that mice deficient in either Akt1 or Akt2 would not respond to in vivo inhibition of ActRIIB with ActRIIB-mFc treatment. METHODOLOGY AND PRINCIPAL FINDINGS: We analyzed body composition and muscle parameters in wild-type C57BL/6J and Akt1 and Akt2 knockout mice, and compared the responses to blockade of ActRIIB signaling via ActRIIB-mFc treatment. Mice lacking Akt1 or Akt2 had reduced muscle mass, grip strength and contractile force. However, deficiency of Akt1 or Akt2 did not prevent the ability of ActRIIB-mFc treatment to induce muscle hypertrophy, or increase grip strength and contractile force. Akt1 and Akt2 deficient mice responded similarly as wild type mice to ActRIIB-mFc treatment by increasing fiber size. CONCLUSIONS AND SIGNIFICANCE: Akt1 and Akt2 are important for the regulation of skeletal muscle mass and function. However, these Akt isoforms are not essential for the ability of ActRIIB inhibition to regulate muscle size, fiber type, strength or contractile force.
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Global ablation of either Akt1 or Akt2 alone did not prevent skeletal muscle hypertrophy induced by treatment with a soluble ActRII decoy receptor.
“A previous study demonstrated that global ablation of either Akt1 or Akt2 alone did not prevent skeletal muscle hypertrophy induced by treatment with a soluble ActRII decoy receptor, suggesting that neither Akt isoform is required [17].”
From Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism (2024) · cites this paper as [17]
Inhibition of ActRII signaling through genetic deletion of muscle ActRIIA/B, antibody blockade of ActRIIA/B, or treatment with a soluble ActRIIB decoy receptor all lead to significant increases in muscle mass.
“Inhibition of ActRII signaling through genetic deletion of muscle ActRIIA/B, antibody blockade of ActRIIA/B, or treatment with a soluble ActRIIB decoy receptor all lead to significant increases in muscle mass [[15], [16], [17]].”
From Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism (2024) · cites this paper as [17]
Whole body Akt1 or Akt2 knockout mice administered a soluble ActRIIB fragment revealed a similar increase in muscle mass across multiple muscle depots in response to ActRIIB inhibition.
“Whole body Akt1 or Akt2 knockout mice administered a soluble ActRIIB fragment revealed a similar increase in muscle mass across multiple muscle depots in response to ActRIIB inhibition [17].”
From Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism (2024) · cites this paper as [17]
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- Authors
- Goncalves, M. D., Pistilli, E. E., Balduzzi, A., Birnbaum, M. J., Lachey, J., Khurana, T. S., & Ahima, R. S.
- Affiliations
- University of Pennsylvania (US)
- Acceleron Pharma (United States) (US)
- Corresponding author
- Ahima, Rexford S.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-09-15
- Volume
- 5
- Issue
- 9
- Pages
- e12707
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2939888
- OpenAlex
- W1967536924
- Cited by
- 69
- References
- 41
- Citations by year
- 2025: 1 · 2024: 5 · 2023: 1 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 7 · 2018: 4 · 2017: 1 · 2016: 4 · 2015: 5 · 2014: 8 · 2013: 7 · 2012: 10
- FWCI
- 2.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of Pennsylvania (P30-DK50306)
- Acceleron
- World Anti-Doping Agency
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK049210, R01DK062348, P30DK50306, P30DK050306)
- 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 › Genetics and Physical Performance
- Keywords
- AKT1, AKT2, skeletal muscle hypertrophy, myostatin, muscle mass, muscle strength, contractile force, muscle fiber size, Akt signaling, knockout mice
- MeSH terms
- Animals, Humans, Male, Mice, Inbred C57BL, Muscle Contraction, Muscular Atrophy, Signal Transduction, Down-Regulation, Mice, Knockout, Muscle, Skeletal, Activin Receptors, Type II, Proto-Oncogene Proteins c-akt, Mice
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