Sathiaseelan 2023 J Gerontol A Biol Sci Med Sci

Sathiaseelan R, Ahn B, Stout MB, Logan S, Wanagat J, Van M Nguyen H, Hord NG, Vandiver AR, Selvarani R, Ranjit R, Yarbrough H, Masingale A, Miller BF, Wolf RF, Austad SN, Richardson A (2023) A genetically heterogeneous rat model with divergent mitochondrial genomes. https://doi.org/10.1093/gerona/glad056

» J Gerontol A Biol Sci Med Sci [Epub ahead of print]. PMID: 36762848 Open Access

Sathiaseelan Roshini, Ahn Bumsoo, Stout Michael B, Logan Sreemathi, Wanagat Jonathan, Nguyen Hoang Van M, Hord Norman G, Vandiver Amy R, Selvarani Ramasamy, Ranjit Rojina, Yarbrough Hannah, Masingale Anthony, Miller Benjamin F, Wolf Roman F, Austad Steven N, Richardson Arlan (2023) J Gerontol A Biol Sci Med Sci

Abstract: We generated a genetically heterogenous rat model by a four-way cross strategy using four inbred strains [Brown Norway (BN), Fischer 344 (F344), Lewis (LEW), and Wistar Kyoto (KY)] to provide investigators with a highly genetically diverse rat model from commercially available inbred rats. We made reciprocal crosses between males and females from the two F1 hybrids to generate genetically heterogeneous rats with mitochondrial genomes from either the BN (OKC-HET^B, a.k.a "B" genotype) or WKY (OKC-HET W a.k.a "W" genotype) parental strains. These two mitochondrial genomes differ at 94 nucleotides, more akin to human mitochondrial genome diversity than that available in classical laboratory mouse strains. Body weights of the B and W genotypes were similar. However, mitochondrial genotype antagonistically affected grip strength and treadmill endurance in females only. In addition, mitochondrial genotype significantly affected multiple responses to a high-fat diet and treatment with 17α-estradiol. Contrary to findings in mice in which males only are affected by 17α-estradiol supplementation, female rats fed a high-fat diet beneficially responded to 17α-estradiol treatment as evidenced by declines in body mass, adiposity, and liver mass. Male rats, by contrast, differed in a mitochondrial genotype-specific manner, with only B males responding to 17α-estradiol treatment. Mitochondrial genotype and sex differences were also observed in features of brain-specific antioxidant response to a high-fat diet and 17α-estradiol as shown by hippocampal levels of Sod2 acetylation, JNK, and FoxO3a. These results emphasize the importance of mitochondrial genotype in assessing responses to putative interventions in aging processes. • Keywords: Aging, Estrogen, Genetic diversity, Mitochondria, Physical function, Sex differences • Bioblast editor: Plangger M • O2k-Network Lab: US NC Winston-Salem Ahn B, US OK Oklahoma City Miller BF

Labels: MiParea: Respiration, mtDNA;mt-genetics 

Organism: Rat  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 

Coupling state: LEAK, OXPHOS  Pathway: N, S, CIV, NS, ROX  HRR: Oxygraph-2k 

2023-02