Ankyrin-B modulates mitochondrial fission in skeletal muscle and is required for optimal endurance exercise capacity

Kayleigh M. Voos, Joyce Tzeng, Priya Patel, Sophie Rubinsky, Ha E. Choi, Trevor Pharr, Sebastian Sookram, Joseph A. Baur, Erik J. Soderblom and Damaris N. Lorenzo ()
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Kayleigh M. Voos: Perelman School of Medicine. University of Pennsylvania
Joyce Tzeng: Perelman School of Medicine. University of Pennsylvania
Priya Patel: Perelman School of Medicine. University of Pennsylvania
Sophie Rubinsky: Perelman School of Medicine. University of Pennsylvania
Ha E. Choi: University of North Carolina at Chapel Hill
Trevor Pharr: University of North Carolina at Chapel Hill
Sebastian Sookram: Perelman School of Medicine. University of Pennsylvania
Joseph A. Baur: Perelman School of Medicine. University of Pennsylvania
Erik J. Soderblom: Duke University
Damaris N. Lorenzo: Perelman School of Medicine. University of Pennsylvania

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract Mitochondrial dynamics enable cellular adaptation to fluctuations in energy demand, such as those imposed on skeletal muscle by exercise, metabolic disorders, or aging. Here, we report a novel pathway that modulates mitochondria dynamics in skeletal muscle involving the scaffolding protein ankyrin-B. Rare variants in ankyrin-B, encoded by ANK2, increase risk for cardio-metabolic syndrome in humans and mice. We show that mice selectively lacking skeletal muscle ankyrin-B have reduced endurance exercise capacity without alterations in muscle strength or systemic glucose regulation. Muscle fibers in these mice have increased oxidative stress, reduced fatty acid oxidation, and enlarged and hyperconnected mitochondria. We found that ankyrin-B interacts with and is required for efficient mitochondria recruitment of fission modulators and sarcoplasmic reticulum-mitochondria coupling. Thus, we conclude that ankyrin-B enables substrate adaptability and bioenergetic homeostasis under energetic stress, and exercise capacity by promoting efficient mitochondrial fission in skeletal muscle.

Date: 2025
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DOI: 10.1038/s41467-025-62977-3

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