2515-P: FoxOs Mediate Mitochondrial Decline, ANT1 Suppression, and Weakness in Response to Insulin and IGF-1 Receptor Deletion in Adult Skeletal Muscle

Eli Stammler; Christie Penniman; Jayashree Jena; Gourav Bhardwaj; Brian O'Neill

doi:10.2337/db26-2515-P

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2515-P: FoxOs Mediate Mitochondrial Decline, ANT1 Suppression, and Weakness in Response to Insulin and IGF-1 Receptor Deletion in Adult Skeletal Muscle

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2515-P: FoxOs Mediate Mitochondrial Decline, ANT1 Suppression, and Weakness in Response to Insulin and IGF-1 Receptor Deletion in Adult Skeletal Muscle

Eli Stammler, Christie Penniman, Jayashree Jena, Gourav Bhardwaj and Brian O'Neill

Diabetes (New York, N.Y.), Vol.75(Suppl 1), p.2515-P

06/01/2026

DOI: 10.2337/db26-2515-P

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Abstract

Introduction and Objective: Skeletal muscle weakness and mitochondrial dysfunction are hallmarks of uncontrolled diabetes. Our prior work showed muscle specific deletion of Insulin receptor (IR) and IGF-1 (IGFR) impairs respiration and ATP production. FoxO transcription factors are activated in response to loss of insulin action and contribute to mitochondrial decline in skeletal muscle. Methods: To define the time dependent effects of IR/IGFR loss and requirement of FoxOs, we tested mitochondrial function in tamoxifen-inducible, muscle-specific IR (Ind-MIRKO) or IR/IGF1R knockout (Ind-MIGIRKO) and performed rescue by combined IR/IGF1R with FoxO1/3/4 quintuple knockout (Ind-QKO) mice. Results: 90 days after tamoxifen KO, Ind-MIRKO mice showed decreased treadmill running and grip strength, but not at Day 21. Permeabilized soleus fiber respiration and ATP production were decreased 33% and 14%, respectively, at Day 90. Ind-MIGIRKO showed decreased grip strength, treadmill, maximal tibialis anterior torque, mitochondrial respiration and ATP production at both Day 21 and 90, all of which was rescued in Ind-QKO. At day 21, Ind-MIGIRKO showed decreased SLC25A4 (aka ANT1) expression by 56%. By day 90, Km of ADP increased by 36% in Ind-MIGIRKO compared to controls indicating decreased ADP sensitivity. However, IC50 using an ANT1 inhibitor was not changed in Ind-MIGIRIKO soleus and re-expression of ANT1 by plasmid electroporation in gastrocnemius did not rescue ATP production in Ind-MIGIRKO mitochondria. Conclusion: Thus, inducible deletion of IR or IR/IGFR in adult muscle causes muscle weakness and mitochondrial dysfunction that is FoxO-dependent. While ANT1 is decreased with IR/IGF1R deletion, restoring ANT1 alone is not sufficient to rescue ATP production.

Insulin

Musculoskeletal System

Diabetes mellitus

Electron transport

Electroporation

Fitness equipment

Forkhead protein

FOXO1 protein

Insulin-like growth factor I

Insulin-like growth factors

Mitochondria

Respiration

Skeletal muscle

Tamoxifen

Transcription factors

Details

Title: Subtitle: 2515-P: FoxOs Mediate Mitochondrial Decline, ANT1 Suppression, and Weakness in Response to Insulin and IGF-1 Receptor Deletion in Adult Skeletal Muscle
Creators: Eli Stammler - University of Iowa, Internal Medicine
Christie Penniman - Iowa City Public Library
Jayashree Jena - Iowa City Public Library
Gourav Bhardwaj - Iowa City Public Library
Brian O'Neill - Iowa City Public Library
Resource Type: Abstract
Publication Details: Diabetes (New York, N.Y.), Vol.75(Suppl 1), p.2515-P
DOI: 10.2337/db26-2515-P
ISSN: 0012-1797
eISSN: 1939-327X
Publisher: American Diabetes Association
Language: English
Date published: 06/01/2026
Academic Unit: Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9985179236602771

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