Effects of aging and caloric restriction on the gene expression of Foxo1, 3, and 4 (FKHR, FKHRL1, and AFX) in the rat skeletal muscles

Furuyama, Tatsuo; Yamashita, Hitoshi; Kitayama, Kenji; Higami, Yoshikazu; Shimokawa, Isao; Mori, Nozomu

doi:10.1002/jemt.10213

Cited by 94 publications

(81 citation statements)

References 12 publications

(11 reference statements)

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“…Our quantitative RT-PCR (qRT-PCR) assay revealed that all family members were robustly expressed in MEFs and in TTFs derived from postnatal and adult mice (Fig. S4), as reported for skeletal muscle (24). We next derived MEFs, and adult TTFs from WT and FoxO3 −/− littermate mice of various age groups.…”

Section: Loss Of Foxo3 Improves Neuronal Conversion Of Fibroblasts Fromsupporting

confidence: 55%

FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice

Ahlenius

Chanda

Webb

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We and others have shown that embryonic and neonatal fibroblasts can be directly converted into induced neuronal (iN) cells with mature functional properties. Reprogramming of fibroblasts from adult and aged mice, however, has not yet been explored in detail. The ability to generate fully functional iN cells from aged organisms will be particularly important for in vitro modeling of diseases of old age. Here, we demonstrate production of functional iN cells from fibroblasts that were derived from mice close to the end of their lifespan. iN cells from aged mice had apparently normal active and passive neuronal membrane properties and formed abundant synaptic connections. The reprogramming efficiency gradually decreased with fibroblasts derived from embryonic and neonatal mice, but remained similar for fibroblasts from postnatal mice of all ages. Strikingly, overexpression of a transcription factor, forkhead box O3 (FoxO3), which is implicated in aging, blocked iN cell conversion of embryonic fibroblasts, whereas knockout or knockdown of FoxO3 increased the reprogramming efficiency of adult-derived but not of embryonic fibroblasts and also enhanced functional maturation of resulting iN cells. Hence, FoxO3 has a central role in the neuronal reprogramming susceptibility of cells, and the importance of FoxO3 appears to change during development.aging | reprogramming | induced neuronal cells R ecent advances in direct reprogramming have demonstrated the feasibility of converting fibroblasts and other terminally differentiated lineages into induced neuronal (iN) cells (1-8). iN cells display elaborate morphologies typical of neurons, express pan-neuronal markers, exhibit hallmarks of functional neurons in that they fire action potentials and form abundant synapses, and, thus, provide a great opportunity for studying the cellular phenotypes of disease-associated genetic mutations (9). To date, most studies used embryonic or early postnatal fibroblasts for reprogramming purposes, but for clinical applications, and in particular for modeling age-related neurodegenerative diseases, it would be preferable to generate iN cells from adult and aged animals.Lineage conversion from aged cells is often challenging, probably due to epigenetic changes during aging. For example, aging has been shown to impair conversion of somatic cells into induced pluripotent stem cells (3,(10)(11)(12). A recent elegant paper demonstrated successful conversion of fibroblasts from old individuals, but cellular properties were not compared between different age groups (13). In embryonic fibroblasts, overexpression of three transcription factors, Brn2, Ascl1, and Myt1l (BAM), efficiently generates iN cells with mature, functional properties within 2 wk (1). Genomic studies and chromatin characterization experiments of fibroblasts shortly after BAM factor expression revealed unique pioneer factor properties of Ascl1, which led to our observation that Ascl1 alone is sufficient to generate functional iN cells, albeit slower and with lower efficiency tha...

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Section: Loss Of Foxo3 Improves Neuronal Conversion Of Fibroblasts Fromsupporting

confidence: 55%

FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice

Ahlenius

Chanda

Webb

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…E2F-1 binds to specific sites in the FoxO1 and FoxO3 promoters (Nowak et al, 2007), indicating that these two FoxO genes are transcriptional targets of E2F-1. FoxO1/3 mRNA levels have been found to increase in muscle from rats that have been either fasted or calorically restricted for 48 h (Furuyama et al, 2002;Imae et al, 2003), suggesting that a nutrient deprivation-induced signaling cascade may also elicit the transcription of FoxO factor genes. However, the transcription factors responsible for the nutrient-inducible transcription of the FoxO genes have not been identified yet.…”

Section: Regulation Of Foxo Protein Stabilitymentioning

confidence: 99%

“…However, the transcription factors responsible for the nutrient-inducible transcription of the FoxO genes have not been identified yet. Interestingly, FoxO3 and FoxO4 mRNAs are modulated as a function of age in rat muscle, peaking at 6 and 12 months respectively (Furuyama et al, 2002), raising the possibility that regulating FoxO levels may affect longevity in mammals. Whether the changes in FoxO mRNA levels in response to nutrients or age are due to changes in transcription or mRNA stability is still unknown.…”

Section: Regulation Of Foxo Protein Stabilitymentioning

confidence: 99%

“…FoxO1 recruits the p300/CBP/SRC co-activator complex in the vicinity of the IGFBP-1 (IGF binding protein 1) promoter in liver cells (Nasrin et al, 2000) and the AgRP (Agouti related protein) promoter in hypothalamic cells . Thus, while the acetylation of FoxO factors by p300/CBP inhibits FoxO function by preventing DNA binding (see above) (Furuyama et al, 2002), the interaction between FoxO and p300/CBP allows the recruitment of a co-activator complex to the promoters of specific genes and initiates transactivation of these genes. This antagonistic role of p300/CBP on FoxO DNA binding and transcriptional activities could be used to fine-tune the levels of expression of FoxO target genes.…”

Section: Recruitment Of Protein Acetylasesmentioning

confidence: 99%

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The FoxO code

2008

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“…It has been reported the expression of FoxO1 gene emerged a temporally restricted manner in the adult and developing mouse brain (Hoekman et al, 2006). Whereas, Furuyama et al (2002) described no signifi cant change with aging in rat skeletal muscles, and reported that the gene expression of FoxO1 was remarkably and selectively induced in mouse skeletal muscle and white adipose tissue with starvation (Furuyama et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

The tissue-specific and developmental expression patterns of the forkhead transcription factor FoxO1 gene in pigs

Liu¹,

Wang²,

Shan³

et al. 2008

J. Anim. Feed Sci.

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The forkhead transcription factor FoxO1 has been studied as the most downstream targets of the signaling pathway in mammals, and played a key role in adipogeneic, cell cycle progression, and energy metabolism and so on. The aim of this study was to investigate the tissue-specifi c and weight-dependent expression patterns of FoxO1 gene in porcine omental adipose tissue and its relation to adipose deposition. Sixty female Duroc × Landrace × Yorkshire pigs in 5 groups, each group containing twelve pigs weighing 1, 20, 40, 60, and 90 kg were used to study developmental expression of FoxO1 gene by means of semi-quantitative RT-PCR. The results showed that FoxO1 mRNA was expressed at a higher level in heart, brain, omental adipose tissue, skeletal muscle, liver and spleen, at a moderate level in kidney, lung, and peritoneal adipose tissue, and at a less level in duodenum, subcutaneous adipose tissue and pancreas. In addition, our data also showed that the expression levels of FoxO1 gene was lowest in the pigs at 20 kg, and continuously increased from 20 to 90 kg body weight (P<0.05). Furthermore, a close positive correlation between the expression levels of FoxO1 gene and the adipose deposition rate was found in pigs (r=0.84, P<0.05).

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Effects of aging and caloric restriction on the gene expression of Foxo1, 3, and 4 (FKHR, FKHRL1, and AFX) in the rat skeletal muscles

Cited by 94 publications

References 12 publications

FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice

FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice

The FoxO code

The tissue-specific and developmental expression patterns of the forkhead transcription factor FoxO1 gene in pigs

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