Transcriptomic Regulation of Muscle Mitochondria and Calcium Signaling by Insulin/IGF-1 Receptors Depends on FoxO Transcription Factors

Bhardwaj, Gourav; Penniman, Christie M.; Klaus, Katherine A.; Weatherford, Eric T.; Hui, Pei; Dreyfuss, Jonathan M.; Nair, K. Sreekumaran; Kahn, C. Ronald; O’Neill, Brian T.

doi:10.3389/fphys.2021.779121

Cited by 9 publications

(11 citation statements)

References 51 publications

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“…In TA, Ndufb8 protein was significantly increase in Aged TKO compared with all other groups whereas other subunits showed less change, but similar patterns to Quad (Figure S9d,e ). Transcriptional regulation of OXPHOS subunits by insulin action is mediated by FoxOs, 26 , 27 so we measured mRNA levels of several OXPHOS subunits in our young and aged groups. Ndufs2, Ndufb8, and Sdhb were significantly decreased in Aged Ctrl Quad when compared with Young Ctrl, but Aged TKO showed no changes.…”

Section: Resultsmentioning

confidence: 99%

“…This makes it difficult to fully assess the role of FoxOs in age‐related sarcopenia. This mild aging phenotype may be due to the mixed genetic background that we described in detail previously, 27 which is a major challenge when using mice to study aging‐related muscle defects. Nonetheless, we do see important decreases in max force generation that are prevented in Aged TKO, which is an important measure of muscle strength in aging.…”

Section: Study Limitationsmentioning

confidence: 99%

“… 25 Despite these controversies, mouse models show that insulin action can directly regulate muscle mitochondrial function in part via FoxOs. 26 , 27 Although FoxOs play a major role in acute muscle atrophy in response to diabetes or starvation, the roles of FoxOs in age‐related muscle strength and mitochondrial function are unknown.…”

Section: Introductionmentioning

confidence: 99%

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Loss of FoxOs in muscle increases strength and mitochondrial function during aging

Penniman

Bhardwaj

Nowers

et al. 2022

J cachexia sarcopenia muscle

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Background Muscle 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. Methods We 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. Results Lean 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. Conclusions FoxO 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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Section: Resultsmentioning

confidence: 99%

Section: Study Limitationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of FoxOs in muscle increases strength and mitochondrial function during aging

Penniman

Bhardwaj

Nowers

et al. 2022

J cachexia sarcopenia muscle

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“…MAPK14, serine/threonine kinase which is one of the 4 p38 MAPKs, p38α MAPK14 is a circadian regulator [53] by phosphorylating various proteins, and it is reported that p38αMAPK inhibitor is efficacious in suppression of synaptic dysfunction in mouse models. [54] IGF1R is upstream of FOXO, [55] while knockdown of BCL2L11 (Bim) or BCL2L1 ectopic expression restrains FOXO3-mediated ROS overproduction and apoptosis. [56] CCL5, formerly known as Regulated on Activation, Normal T Cell Expressed and Presumably Secreted, is one of the CC subfamily of chemokines and plays a role in the peripheral immune system.…”

Section: Discussionmentioning

confidence: 99%

Molecular targets and mechanisms involved in the action of Banxia Shumi decoction in insomnia treatment

Zhang

Zhang²,

Wang³

et al. 2023

Medicine

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Insomnia is a common sleep-wake rhythm disorder, which is closely associated with the occurrence of many serious diseases. Recent researches suggest that circadian rhythms play an important role in regulating sleep duration and sleep quality. Banxia Shumi decoction (BSXM) is a well-known Chinese formula used to treat insomnia in China. However, the overall molecular mechanism behind this therapeutic effect has not yet been fully elucidated. This study aimed to identify the molecular targets and mechanisms involved in the action of BSXM during the treatment of insomnia. Using network pharmacology and molecular docking methods, we investigated the molecular targets and underlying mechanisms of action of BSXM in insomnia therapy. We identified 8 active compounds from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and the traditional Chinese medicine integrative database that corresponded to 26 target genes involved in insomnia treatment. The compound-differentially expressed genes of the BXSM network indicated that cavidine and gondoic acid could potentially become key components of drugs used for insomnia treatment. Further analysis revealed that GSK3B, MAPK14, IGF1R, CCL5, and BCL2L11 were core targets significantly associated with the circadian clock. Pathway enrichment analysis of Kyoto Encyclopedia of Genes and Genomes revealed that epidermal growth factor receptor tyrosine kinase inhibitor resistance was the most prominently enriched pathway for BSXM in the insomnia treatment. The forkhead box O signaling pathway was also found to be significantly enriched. These targets were validated using the Gene Expression Omnibus dataset. Molecular docking studies were performed to confirm the binding of cavidine and gondoic acid to the identified core targets. To our knowledge, our study confirmed for the first time that the multi-component, multi-target, and multi-pathway characteristics of BXSM may be the potential mechanism for treating insomnia with respect to the circadian clock gene. The results of this study provided theoretical guidance for researchers to further explore its mechanism of action.Abbreviations: BCL2L1 = BCL2 like 1, BSXM = Banxia Shumi decoction, DEGs = differentially expressed genes, EGFR = epidermal growth factor receptor, FOXO = forkhead box O, GO = gene ontology, GA = gondoic acid, GSEA = gene set enrichment analysis, KEGG = Kyoto Encyclopedia of Genes and Genomes, MAPK14 = mitogen-activated protein kinase, MCC = maximum cluster centrality, PPI = protein-protein interaction, ROC = receiver operating characteristic, SD = sleep deprivation, TCM = traditional Chinese medicine.

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“…The PI3K/Akt pathway was early proved involved in the anti-apoptotic effects of estrogen mediated by ER-α and ER-β in skeletal muscle cells, especially at the mitochondrial level ( 57 , 58 ). FoxO transcription factors are strongly implicated to multiple regulatory and signaling pathways of oxidative phosphorylation, inflammatory signaling, TCA cycle, and mitochondrial function ( 59 ). It was found that muscle atrophy could be ameliorated by regulating myostatin-mediated PI3K/Akt/FoxO3a pathway and satellite cell function in chronic kidney disease ( 60 ).…”

Section: Discussionmentioning

confidence: 99%

An integrated study of hormone-related sarcopenia for modeling and comparative transcriptome in rats

et al. 2023

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Sarcopenia is a senile disease with high morbidity, serious complications and limited clinical treatments. Menopause increases the risk of sarcopenia in females, while the exact pathogenesis remains unclear. To systematically investigate the development of hormone-related sarcopenia, we established a model of sarcopenia by ovariectomy and recorded successive characteristic changes. Furthermore, we performed the transcriptome RNA sequencing and bioinformatics analysis on this model to explore the underlying mechanism. In our study, we identified an integrated model combining obesity, osteoporosis and sarcopenia. Functional enrichment analyses showed that most of the significantly enriched pathways were down-regulated and closely correlated with endocrine and metabolism, muscle dysfunction, cognitive impairment and multiple important signaling pathways. We finally selected eight candidate genes to verify their expression levels. These findings confirmed the importance of estrogen in the maintenance of skeletal muscle function and homeostasis, and provided potential targets for further study on hormone-related sarcopenia.

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Transcriptomic Regulation of Muscle Mitochondria and Calcium Signaling by Insulin/IGF-1 Receptors Depends on FoxO Transcription Factors

Cited by 9 publications

References 51 publications

Loss of FoxOs in muscle increases strength and mitochondrial function during aging

Loss of FoxOs in muscle increases strength and mitochondrial function during aging

Molecular targets and mechanisms involved in the action of Banxia Shumi decoction in insomnia treatment

An integrated study of hormone-related sarcopenia for modeling and comparative transcriptome in rats

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