Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance
Open accessAbstract
Aging-associated muscle insulin resistance has been hypothesized to be due to decreased mitochondrial function, secondary to cumulative free radical damage, leading to increased intramyocellular lipid content. To directly test this hypothesis, we examined both in vivo and in vitro mitochondrial function, intramyocellular lipid content, and insulin action in lean healthy mice with targeted overexpression of the human catalase gene to mitochondria (MCAT mice). Here, we show that MCAT mice are protected from age-induced decrease in muscle mitochondrial function (∼30%), energy metabolism (∼7%), and lipid-induced muscle insulin resistance. This protection from age-induced reduction in mitochondrial function was associated with reduced mitochondrial oxidative damage, preserved mitochondrial respiration and muscle ATP synthesis, and AMP-activated protein kinase-induced mitochondrial biogenesis. Taken together, these data suggest that the preserved mitochondrial function maintained by reducing mitochondrial oxidative damage may prevent age-associated whole-body energy imbalance and muscle insulin resistance.
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Dysfunctional mitochondria accumulate with age, most clearly in tissues composed mainly of post-mitotic cells.
“Dysfunctional mitochondria accumulate with age, best documented in tissues comprised largely of post-mitotic cells”
From Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype (2016) · cites this paper as Lee et al., 2010
The Results (page unavailable) report age-associated reductions in muscle mitochondrial function in old mice, supporting the claim's general point about aging and dysfunction. They do not establish that dysfunctional mitochondria accumulate or that the pattern is best documented in largely post-mitotic tissues; the reported mitochondrial density in soleus muscle decreased with age. (LLM, conf=0.84)
Experimental — accuracy not yet measuredGenetic or pharmacological manipulations that lower mitochondrial ROS production preserve insulin action in lipid-treated myotubes and in mice fed a high-fat diet.
“genetic or pharmacological manipulations that lowered mitochondrial ROS production preserved insulin action in lipid-treated myotubes (Hoehn et al., 2009) and in mice fed a high fat diet (Anderson et al., 2009; Hoehn et al., 2009; Lee et al., 2010).”
From Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle (2012) · cites this paper as Lee et al., 2010
Aged wild type mice develop muscle insulin resistance associated with increased muscle lipid (TAG/DAG) content (but no change in ceramide) and reduced muscle mitochondrial function.
“Like humans, it was found that aged wild type mice develop muscle insulin resistance, which was associated with increased muscle lipid (TAG/DAG) content (but no change in muscle ceramide content) and reduced muscle mitochondrial function.”
From Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging (2020) · cites this paper as Lee et al., 2010
Effects of aging were abrogated in mice with targeted overexpression of catalase to mitochondria.
“Interestingly, all these effects of aging were abrogated in mice with targeted overexpression of catalase to the mitochondria.”
From Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging (2020) · cites this paper as Lee et al., 2010
There is substantial evidence of increased ROS production and oxidative stress-induced damage to mtDNA and ETC complexes in aged rodents and non-human primates, as well as in human vastus lateralis muscle.
“there is substantial evidence showing increased ROS production and associated oxidative stress-induced damage to mitochondrial DNA (mtDNA) and ETC complexes in aged rodents and non-human primates (Figueiredo, Powers, Ferreira, Appell, and Duarte 2009;Lee, Choi, Birkenfeld, Alves, Jornayvaz, Jurczak, Zhang, Woo, Shadel, and Ladiges 2010;Lee, Wang, and Fanburg 1998;WANAGAT, CAO, PATHARE, and AIKEN 2”
From Successful aging: Advancing the science of physical independence in older adults (2015) · cites this paper as Lee et al. 2010
These same mice are protected from mitochondrial dysfunction, decreased energy metabolism and lipid-induced insulin resistance in skeletal muscle.
“These same mice are also protected from mitochondrial dysfunction, decreased energy metabolism and lipid-induced insulin resistance in skeletal muscle (Lee et al., 2010).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Lee et al., 2010
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- Authors
- Lee, H.-Y., Choi, C. S., Birkenfeld, A. L., Alves, T. C., Jornayvaz, F. R., Jurczak, M. J., Zhang, D., Woo, D. K., Shadel, G. S., Ladiges, W., Rabinovitch, P. S., Santos, J. H., Petersen, K. F., Samuel, V. T., & Shulman, G. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- Gachon University (KR)
- Yale University (US)
- University of Washington (US)
- Rutgers New Jersey Medical School (US)
- Corresponding author
- Shulman, Gerald I.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 12
- Issue
- 6
- Pages
- 668-674
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3013349
- OpenAlex
- W2056525347
- Cited by
- 319
- References
- 38
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 17 · 2023: 7 · 2022: 16 · 2021: 15 · 2020: 21 · 2019: 22 · 2018: 20 · 2017: 16 · 2016: 26 · 2015: 28 · 2014: 38 · 2013: 26 · 2012: 33
- FWCI
- 10.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 959 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- PubMed Central (acceptedVersion)
- Site cant be reached (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- U.S. Department of Veterans Affairs
- U.S. Public Health Service (P01 AG001751, P01 ES01116, R01 AG23686, R01 DK40936, U24 DK076169)
- Deutsche Forschungsgemeinschaft (Bi1292/2-1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- catalase, mitochondrial targeting, muscle aging, insulin resistance, mitochondrial function, oxidative damage, intramyocellular lipid, energy metabolism, AMPK, mitochondrial biogenesis, ATP production, free radicals
- MeSH terms
- Adenosine Triphosphate, Aging, Animals, Catalase, DNA Damage, Energy Metabolism, Humans, Insulin, Insulin Resistance, Male, Mice, Transgenic, Mitochondria, Oxygen Consumption, Reactive Oxygen Species, Oxidative Stress, Muscle, Skeletal, Microscopy, Electron, Transmission, Mice
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