ArticleJournal of cachexia, sarcopenia and muscle2023
Loss of FoxOs in muscle increases strength and mitochondrial function during aging.
Article in Journal of cachexia, sarcopenia and muscle, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 34 citations in OpenAlex.
- Maslinic Acid Alleviates Obesity-Associated Skeletal Muscle Atrophy and Adipose Tissue Dysfunction in Obese Mice.Biomolecules & therapeutics · 2026Article
- Therapeutic potential of ginseng and ginsenosides on muscle wasting disorders: Cachexia, sarcopenia, anorexia, and aging.Journal of ginseng research · 2026Review
- Plant‑derived natural products alleviate dexamethasone‑induced skeletal muscle atrophy by modulating FoxO (Review).International journal of molecular medicine · 2026Review
- Circulating PBX1 and age-related sarcopenia phenotypes: metabolic mediation analyses in a community-based study.European geriatric medicine · 2026Article
- Review
- Activation of α7nAChR reduces inflammation and apoptosis, promoting muscle regeneration through the AKT-FOXO1 pathway.Cell death and differentiation · 2026Article
- Hot melt extruded Kyungohkgo attenuates skeletal muscle atrophy by downregulating the FOXO3a/MuRF-1/atrogin-1 axis.Scientific reports · 2026Article
- Studies of Foxo1 over the Past 25 Years: Mechanisms of Insulin Resistance and Glucose Dysregulation.Cells · 2026Review
- PDHA1 Hyperactivation Orchestrates Metabolic Reprogramming Promoting Endothelial Senescence.Research (Washington, D.C.) · 2026Article
- Exercise suppresses DEAF1 to normalize mTORC1 activity and reverse muscle aging.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Molecular Framework of the Onset and Progression of Skeletal Muscle Aging.International journal of molecular sciences · 2025Review
- Effects and Mechanisms of Long-TermFoods (Basel, Switzerland) · 2025Article
- Transcriptional Response to Fasting Studied in the Liver of Mice That Express Phosphorylation Resistant Perilipin 5.Endocrinology · 2025Article
- Texture analysis of T1- and T2-weighted images identifies myofiber atrophy and grip strength decline in streptozotocin-induced type 1 diabetic sarcopenia rats.Journal of orthopaedic surgery and research · 2025Article
- Sarcopenia and cognitive impairment: a multidimensional study of clinical associations, shared genetics, and causal links.Frontiers in aging neuroscience · 2025Article
- High-Intensity Interval Training Mitigates Sarcopenia and Suppresses the Myoblast Senescence Regulator EEF1E1.Journal of cachexia, sarcopenia and muscle · 2024Article
- Betaine delays age-related muscle loss by mitigating Mss51-induced impairment in mitochondrial respiration via Yin Yang1.Journal of cachexia, sarcopenia and muscle · 2024Article
- Ubiquitination Insight from Spinal Muscular Atrophy-From Pathogenesis to Therapy: A Muscle Perspective.International journal of molecular sciences · 2024Review
- Cancerous Conditions Accelerate the Aging of Skeletal Muscle via Mitochondrial DNA Damage.International journal of molecular sciences · 2024Article
- Regulation of mitochondrial function by FOXOs in ischemic stroke and Alzheimer's disease.Organelle (Tucson, Ariz.) · 2024Article
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Authors and funding
10 authors at 1 institution in 1 country.
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Abstract
backgroundMuscle mitochondrial decline is associated with aging-related muscle weakness and insulin resistance. FoxO transcription factors are targets of insulin action and deletion of FoxOs improves mitochondrial function in diabetes. However, disruptions in proteostasis and autophagy are hallmarks of aging and the effect of chronic inhibition of FoxOs in aged muscle is unknown. This study investigated the role of FoxOs in regulating muscle strength and mitochondrial function with age.
methodsWe measured muscle strength, cross-sectional area, muscle fibre-type, markers of protein synthesis/degradation, central nuclei, glucose/insulin tolerance, and mitochondrial bioenergetics in 4.5-month (Young) and 22-24-month-old (Aged) muscle-specific FoxO1/3/4 triple KO (TKO) and littermate control (Ctrl) mice.
resultsLean mass was increased in Aged TKO compared with both Aged Ctrl and younger groups by 26-33% (P < 0.01). Muscle strength, measured by max force of tibialis anterior (TA) contraction, was 20% lower in Aged Ctrl compared with Young Ctrls (P < 0.01) but was not decreased in Aged TKOs. Increased muscle strength in Young and Aged TKO was associated with 18-48% increased muscle weights compared with Ctrls (P < 0.01). Muscle cross-sectional analysis of TA, soleus, and plantaris revealed increases in fibre size distribution and a 2.5-10-fold increase in central nuclei in Young and Aged TKO mice, without histologic signs of muscle damage. Age-dependent increases in Gadd45a and Ube4a expression as well accumulation of K48 polyubiquitinated proteins were observed in quad and TA but were prevented by FoxO deletion. Young and Aged TKO muscle showed minimal changes in autophagy flux and no accumulation of autophagosomes compared with Ctrl groups. Increased strength in Young and Aged TKO was associated with a 10-20% increase in muscle mitochondrial respiration using glutamate/malate/succinate compared with controls (P < 0.05). OXPHOS subunit expression and complex I activity were decreased 16-34% in Aged Ctrl compared with Young Ctrl but were prevented in Aged TKO. Both Aged Ctrl and Aged TKO showed impaired glucose tolerance by 33% compared to young groups (P < 0.05) indicating improved strength and mitochondrial respiration are not due to improved glycemia.
conclusionsFoxO deletion increases muscle strength even during aging. Deletion of FoxOs maintains muscle strength in part by mild suppression of atrophic pathways, including inhibition of Gadd45a and Ube4a expression, without accumulation of autophagosomes in muscle. Deletion of FoxOs also improved mitochondrial function by maintenance of OXPHOS in both young and aged TKO.
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