Metformin Treatment in Old Rats and Effects on Mitochondrial Integrity

Herbst, Allen; Hoang, Austin; Kim, Chiye; Aiken, Judd M.; McKenzie, Debbie; Goldwater, Deena; Wanagat, Jonathan

doi:10.1089/rej.2021.0052

Cited by 8 publications

(2 citation statements)

References 48 publications

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“…Digital PCR is not dependent on or affected by the amplification efficiency of the PCR primers or other confounders of quantitative PCR methods [ 34 ]. Specific primer/probe sets were used for each target as previously described [ 35 ] and illustrated in Fig 1B . MtDNA deletion frequency is the proportion of mutant molecules per wild-type mtDNA molecules.…”

Section: Methodsmentioning

confidence: 99%

Remdesivir does not affect mitochondrial DNA copy number or deletion mutation frequency in aged male rats: A short report

Herbst

Choi²,

Hoang³

et al. 2022

PLoS ONE

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Remdesivir is a leading therapy in patients with moderate to severe coronavirus 2 (SARS-CoV-2) infection; the majority of whom are older individuals. Remdesivir is a nucleoside analog that incorporates into nascent viral RNA, inhibiting RNA-directed RNA polymerases, including that of SARS-CoV-2. Less is known about remdesivir’s effects on mitochondria, particularly in older adults where mitochondria are known to be dysfunctional. Furthermore, its effect on age-induced mitochondrial mutations and copy number has not been previously studied. We hypothesized that remdesivir adversely affects mtDNA copy number and deletion mutation frequency in aged rodents. To test this hypothesis, 30-month-old male F333BNF1 rats were treated with remdesivir for three months. To determine if remdesivir adversely affects mtDNA, we measured copy number and mtDNA deletion frequency in rat hearts, kidneys, and skeletal muscles using digital PCR. We found no effects from three months of remdesivir treatment on mtDNA copy number or deletion mutation frequency in 33-month-old rats. These data support the notion that remdesivir does not compromise mtDNA quality or quantity at old age in mammals. Future work should focus on examining additional tissues such as brain and liver, and extend testing to human clinical samples.

show abstract

Section: Methodsmentioning

confidence: 99%

Remdesivir does not affect mitochondrial DNA copy number or deletion mutation frequency in aged male rats: A short report

Herbst

Choi²,

Hoang³

et al. 2022

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…A 5-prime nuclease cleavage assay and droplet-based digital PCR (dPCR) were used to quantitate copy numbers for nuclear DNA (nDNA), total mtDNA, and mtDNA deletion mutations, with specific primer/probe sets for each as previously described [30]. MtDNA deletion frequency is the proportion of mutant molecules per wild-type mtDNA.…”

Section: Mtdna Copy Number and Mtdna Deletion Frequency By Digital Pcrmentioning

confidence: 99%

Remdesivir does not affect mitochondrial DNA copy number or deletion mutation frequency in aged male rats

Herbst

Choi²,

Hoang³

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Remdesivir is a leading therapy in patients with moderate to severe coronavirus 2 (SARS-CoV-2) infection; the majority of whom are older individuals. Remdesivir is a nucleoside analog that incorporates into nascent viral RNA, inhibiting RNA-directed RNA polymerases, including that of SARS-CoV-2. Less is known about remdesivir's effects on mitochondria, particularly in older adults where mitochondria are known to be dysfunctional. Furthermore, its effect on age-induced mitochondrial mutations and copy number has not been previously studied. We hypothesized that remdesivir adversely affects mtDNA copy number and deletion mutation frequency in aged rodents. To test this hypothesis, 30-month-old male F333BNF1 rats were treated with remdesivir for three months. To determine if remdesivir adversely affects mtDNA, we measured copy number and mtDNA deletion frequency in rat hearts, kidneys, and skeletal muscles using digital PCR. We found no effects from three months of remdesivir treatment on mtDNA copy number or deletion mutation frequency in 33-month-old rats. For the 33-month-old control rats, the average mtDNA copy number per nucleus was 2567, 1100, and 1869 for heart, kidney, and quadriceps, respectively. MtDNA deletion mutation frequency was 2.6x10 -4 , 1.6x10 -4 and 4.7x10 -3 for heart, kidney, and quadriceps, respectively. These data support the notion that remdesivir does not compromise mtDNA quality or quantity at old age in mammals. Future work should focus on examining additional tissues such as brain and liver, and extend testing to human clinical samples.

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Age-induced changes in skeletal muscle mitochondrial DNA synthesis, quantity, and quality in genetically unique rats

Musci,

Fuqua,

Peelor

et al. 2024

GeroScience

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Mitochondrial genomic integrity is a key element of physiological processes and health. Changes in the half-life of the mitochondrial genome are implicated in the generation and accumulation of age-induced mitochondrial DNA (mtDNA) mutations, which are implicated in skeletal muscle aging and sarcopenia. There are conflicting data on the half-life of mtDNA, and there is limited information on how aging affects half-life in skeletal muscle. We hypothesized that skeletal muscle mtDNA synthesis rates would decrease with age in both female and male rats concomitant with changes in mtDNA integrity reflected in mtDNA copy number and mutation frequency. We measured mitochondrial genome half-life using stable isotope labeling over a period of 14 days and assessed mtDNA copy number and deletion mutation frequency using digital PCR in the quadriceps muscle of 9-month-old and 26-month-old male and female OKC-HET rats. We found a significant age-related increase in mtDNA half-life, from 132 days at 9 months to 216 days at 26 months of age in OKC-HET quadriceps. Concomitant with the increase in mtDNA half-life, we found an age-related increase in mtDNA deletion mutation frequency in both male and female rats. Notably, 26-month-old female rats had a lower mutation frequency than male rats, and there were no changes in mtDNA copy number with sex, age, or mitochondrial genotype. These data reveal several key findings: (1) mtDNA turnover in rat skeletal muscle decreases with age, (2) mtDNA half-lives in skeletal muscle are approximately an order of magnitude longer than what is reported for other tissues, and (3) muscle mtDNA turnover differs significantly from the turnover of other mitochondrial macromolecules including components of the mitochondrial nucleoid. These findings provide insight into the factors driving age-induced mtDNA mutation accumulation, which contribute to losses of mitochondrial genomic integrity and may play a role in skeletal muscle dysfunction.

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Metformin Treatment in Old Rats and Effects on Mitochondrial Integrity

Cited by 8 publications

References 48 publications

Remdesivir does not affect mitochondrial DNA copy number or deletion mutation frequency in aged male rats: A short report

Remdesivir does not affect mitochondrial DNA copy number or deletion mutation frequency in aged male rats: A short report

Remdesivir does not affect mitochondrial DNA copy number or deletion mutation frequency in aged male rats

Age-induced changes in skeletal muscle mitochondrial DNA synthesis, quantity, and quality in genetically unique rats

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