Ankyrin-B modulates mitochondrial fission in skeletal muscle and is required for optimal endurance exercise capacity
Year: 2025
Type: article
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. Scaffolding protein ankyrin-B, implicated in cardiometabolic syndrome, enables mitochondrial fission and flexibility of nutrient utilization under energetic stress in skeletal muscle to support energy production and optimal exercise capacity.
Source: Nature Communications
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Health and Human Services, American Diabetes Association, University of Pennsylvania, Johns Hopkins University, National Institutes of Health, Intellectual and Developmental Disabilities Research Center, University of North Carolina at Chapel Hill, Nutrition Obesity Research Center, University of North Carolina, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Penn Center for Musculoskeletal Disorders, National Opinion Research Center
Awards: G1236714046, G1880809784, G1900992964, G1989292043, Indirect calorimetry cages equipped for glucose and blood pressure telemetry, G2904135903, G296085590, Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging, G435235180, G4588794352, Elucidating the synaptic interactome of the high risk autism gene ANK2, G5351521234, Understanding the roles of cardiac NAD pools and therapeutic effects of precursor supplements in heart failure, G5468254272, G6074747248, Role of Ankyrin-B in the Nervous System, G7227154987, Molecular mechanisms of ankyrins in the regulation of glucose homeostasis –metabolic consequences of type 2 diabetes ankyrin risk variants, G8411208754, G867308462, G9000027353, G9000031743, G9000041240, G9000073610, G9000119884, G9000297850, G9000347941, Overall: Resource-based Center for Musculoskeletal Disorders Research (Overall Application), University of Pennsylvania Diabetes Research Center, Nutrition Obesity Research Center (NORC), G950284202
OpenAlex ID: W4413495268