Mitochondrial dysfunction/NLRP3 inflammasome axis contributes to angiotensin II-induced skeletal muscle wasting via PPAR-γ
Open accessAbstract
Angiotensin II (Ang II) levels are elevated in patients with chronic kidney disease or heart failure, and directly causes skeletal muscle wasting in rodents, but the molecular mechanisms of Ang II-induced skeletal muscle wasting and its potential as a therapeutic target are unknown. We investigated the NLR family pyrin domain containing 3 (NLRP3) inflammasome-mediated muscle atrophy response to Ang II in C2C12 myotubes and Nlrp3 knockout mice. We also assessed the mitochondrial dysfunction (MtD)/NLRP3 inflammasome axis in Ang II-induced C2C12 myotubes. Finally, we examined whether a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist could attenuate skeletal muscle wasting by targeting the MtD/NLRP3 inflammasome axis in vitro and in vivo. We demonstrated that Ang II increased NLRP3 inflammasome activation in cultured C2C12 myotubes dose dependently. Nlrp3 knockdown or Nlrp3-/- mice were protected from the imbalance of protein synthesis and degradation. Exposure of C2C12 to Ang II increased mitochondrial ROS (mtROS) generation, accompanied by MtD. Remarkably, the mitochondrial-targeted antioxidant not only decreased mtROS and MtD, it also significantly inhibited NLRP3 inflammasome activation and restored skeletal muscle atrophy. Finally, the PPAR-γ agonist protected against Ang II-induced muscle wasting by preventing MtD, oxidative stress, and NLRP3 inflammasome activation in vitro and in vivo. This work suggests a potential role of MtD/NLRP3 inflammasome pathway in the pathogenesis of Ang II-induced skeletal muscle wasting, and targeting the PPAR-γ/MtD/NLRP3 inflammasome axis may provide a therapeutic approach for muscle wasting.
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Alterations in mPTP function contribute to the aging-related loss of muscle mass and function.
“Alterations in mPTP function are undoubtedly contributing to the aging-related loss of muscle mass and function, since mPTP opening can trigger several atrophy-regulating pathways.”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [19]
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Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging
Leduc-Gaudet, J.-P., Hussain, S. N. A., Barreiro, E., & Gouspillou, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158179 · Cited by 268 · see citing works
“Second, mPTP opening can result in mitochondrial DNA release and consequential activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome, which was shown to increase the expression of ubiquitin ligases involved in muscle atrophy [18,19].”
Background
- Authors
- Liu, Y., Bi, X., Zhang, Y., Wang, Y., & Ding, W.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Ding, Wei
- Venue
- Laboratory Investigation
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 100
- Issue
- 5
- Pages
- 712-726
- ISSN
- 0023-6837 (ISSN-L)
- OpenAlex
- W2996604018
- Cited by
- 48
- References
- 36
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 5 · 2023: 6 · 2022: 8 · 2021: 13 · 2020: 2
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Laboratory Investigation (publishedVersion)
- SSRN Electronic Journal (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- angiotensin II, skeletal muscle atrophy, NLRP3 inflammasome, mitochondrial dysfunction, PPARγ agonists, mitochondrial reactive oxygen species, oxidative stress, muscle atrophy, protein synthesis and degradation, chronic kidney disease, heart failure, NLRP3 knockout mice, C2C12 myotubes
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Angiotensin II, Animals, Cell Line, Mice, Inbred C57BL, Mitochondria, Muscular Atrophy, Mice, Knockout, Muscle, Skeletal, PPAR gamma, Mice
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