2439-P: Activation of FOXO1 Impairs Muscle Mitochondrial Respiration and Strength prior to Decreased Mass

Christie Penniman; Jayashree Jena; Vitor Lira; Gourav Bhardwaj; Brian O'Neill

doi:10.2337/db26-2439-P

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2439-P: Activation of FOXO1 Impairs Muscle Mitochondrial Respiration and Strength prior to Decreased Mass

Abstract

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2439-P: Activation of FOXO1 Impairs Muscle Mitochondrial Respiration and Strength prior to Decreased Mass

Christie Penniman, Jayashree Jena, Vitor Lira, Gourav Bhardwaj and Brian O'Neill

Diabetes (New York, N.Y.), Vol.75(Suppl 1), p.2439-P

06/01/2026

DOI: 10.2337/db26-2439-P

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Abstract

Introduction and Objective: Insulin-deficient diabetes is characterized by decreased muscle mass, mitochondrial dysfunction, and defective oxidative metabolism. FOXO1/3/4 transcription factors have emerged as major regulators of diabetes-induced muscle atrophy and mitochondrial dysfunction. However, the specific contribution of each FOXO to mitochondrial metabolism remains unclear. Methods: To elucidate the role of FoxO1 in skeletal muscle, we generated C2C12 cell lines overexpressing either a dominant negative FOXO1 (DNFOXO1, lacking the transactivation domain) or a constitutively active FoxO1 (CAFOXO1, with 3 mutated Akt phosphorylation sites). Results: DN-FOXO1 overexpression blocked the induction of FOXO-dependent atrophy genes, including Gadd45a, Gabarapl1, and MuRF1 during serum starvation, but did not affect mitochondrial function. By contrast, CA-FOXO1 reduced mitochondrial respiration, and downregulated OXPHOS subunits Ndufv2 and Sdhb by 12 and 24%, respectively. To evaluate effects in vivo, we overexpressed CA-FOXO1 in mouse tibialis anterior (TA) muscle via electroporation, achieving a five-fold overexpression of protein levels. CA-FOXO1 reduced mitochondrial genes Ndusf1 by 22%, and Ndufv2 by 33%, and induced FOXO1 targets Gadd45a, Gabarapl1, and MuRF1. Mitochondrial functional measurements showed a 45% decrease in mitochondrial respiration and 23% reduction in ATP production using pyruvate/malate substrates 2 weeks after electroporation. Despite unchanged muscle size, tetanic force decreased by 29%, showing impaired muscle strength associated with mitochondrial decline. Conclusion: These data demonstrate that FOXO1 activation represses mitochondrial genes and impairs mitochondrial function in skeletal muscle after just 2 weeks of expression, prior to measurable atrophy, and could affect muscle strength in uncontrolled diabetes.

Cell Lines

Diabetes

Metabolism

Musculoskeletal System

Phosphorylation

Protein Folding

AKT protein

Atrophy

Diabetes mellitus

Electron transport

Electroporation

Forkhead protein

FOXO1 protein

Gadd45A protein

Mitochondria

Muscle strength

Oxidative metabolism

Pyruvic acid

Respiration

Skeletal muscle

Transcription activation

Transcription factors

Details

Title: Subtitle: 2439-P: Activation of FOXO1 Impairs Muscle Mitochondrial Respiration and Strength prior to Decreased Mass
Creators: Christie Penniman - Iowa City Public Library
Jayashree Jena - Iowa City Public Library
Vitor Lira - 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.2439-P
DOI: 10.2337/db26-2439-P
ISSN: 0012-1797
eISSN: 1939-327X
Publisher: American Diabetes Association
Language: English
Date published: 06/01/2026
Academic Unit: Dental Research; Endocrinology and Metabolism; Health, Sport, and Human Physiology ; Internal Medicine
Record Identifier: 9985179099102771

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