Dietary phosphorus restriction enables multigenerational breeding of α-Klotho-deficient rats
- 1Jichi Medical University
Abstract
Severe -Klotho deficiency causes early mortality and reproductive impairment, limiting the maintenance and physiological analysis of rat models. We generated rats carrying a CRISPR/Cas9-mediated -Klotho deletion spanning exons 1-5 and evaluated dietary phosphorus restriction primarily in the Wistar-Imamichi background. Maternal low-phosphorus (LP) feeding from mating through lactation was associated with higher overall survival to weaning (92.6% versus 85.8% under normal-phosphorus conditions) and a higher proportion of KO animals among weaned survivors (34/113 versus 23/145). Maternal LP feeding also reduced plasma phosphorus in KO pups. Continued LP feeding after weaning supported growth, gonadal development, and natural KO x KO breeding. Across 15 litters, 74 of 85 offspring survived to weaning, and KO colonies were maintained to at least the fifth generation. We additionally characterized 24-h metabolic rhythms in LP-maintained KO animals using indirect calorimetry. These profiles remained heterogeneous under a light-dark cycle. In conclusion, dietary phosphorus restriction provides a reliable strategy for the multigenerational maintenance of severe -Klotho-deficient rats, establishing a maintainable model to investigate residual metabolic and physiological phenotypes.
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BibTeX
@misc{sarai2026dietary,
title = {{Dietary phosphorus restriction enables multigenerational breeding of α-Klotho-deficient rats}},
author = {C. Sarai and Y. Totsuka and T. Horii and S. Tamura and E. Gouda and S. Kojima and T. Kouki and N. Ohno and A. Yoshiki and T. Ohmori and H. Kurosu and H. Endo and K. Tominaga and I. Hatada and T. Yamamoto and M. Kuro-o and Y. Nagao},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.17.759802},
url = {https://www.biorxiv.org/content/10.64898/2026.10.17.759802v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Dietary phosphorus restriction enables multigenerational breeding of α-Klotho-deficient rats
AU - C. Sarai
AU - Y. Totsuka
AU - T. Horii
AU - S. Tamura
AU - E. Gouda
AU - S. Kojima
AU - T. Kouki
AU - N. Ohno
AU - A. Yoshiki
AU - T. Ohmori
AU - H. Kurosu
AU - H. Endo
AU - K. Tominaga
AU - I. Hatada
AU - T. Yamamoto
AU - M. Kuro-o
AU - Y. Nagao
PY - 2026
DA - 2026/10/17
PB - bioRxiv
DO - 10.64898/2026.10.17.759802
UR - https://www.biorxiv.org/content/10.64898/2026.10.17.759802v1
AB - Severe -Klotho deficiency causes early mortality and reproductive impairment, limiting the maintenance and physiological analysis of rat models. We generated rats carrying a CRISPR/Cas9-mediated -Klotho deletion spanning exons 1-5 and evaluated dietary phosphorus restriction primarily in the Wistar-Imamichi background. Maternal low-phosphorus (LP) feeding from mating through lactation was associated with higher overall survival to weaning (92.6% versus 85.8% under normal-phosphorus conditions) and a higher proportion of KO animals among weaned survivors (34/113 versus 23/145). Maternal LP feeding also reduced plasma phosphorus in KO pups. Continued LP feeding after weaning supported growth, gonadal development, and natural KO x KO breeding. Across 15 litters, 74 of 85 offspring survived to weaning, and KO colonies were maintained to at least the fifth generation. We additionally characterized 24-h metabolic rhythms in LP-maintained KO animals using indirect calorimetry. These profiles remained heterogeneous under a light-dark cycle. In conclusion, dietary phosphorus restriction provides a reliable strategy for the multigenerational maintenance of severe -Klotho-deficient rats, establishing a maintainable model to investigate residual metabolic and physiological phenotypes.
ER -