4 replies to this topic

[CaptainFuture]

This study was done on mice but it's still fascinating.

http://www.scienceda...20229105135.htm


No Workout? No Worries: Scientists Prevent Muscle Loss in Mice, Despite Disease and Inactivity

ScienceDaily (Feb. 29, 2012) — If you want big muscles without working out, there's hope. In the March 2012 print issue of the FASEB Journal, scientists from the University of Florida report that a family of protein transcription factors, called "Forkhead (Fox0)" plays a significant role in the regulation of skeletal muscle mass. Specifically, they found that interfering with the activity of these transcription factors prevents muscle wasting associated with cancer and sepsis, and even promotes muscle growth. This discovery is likely to be relevant to any disease, condition or lifestyle that leads to muscle wasting, including voluntary inactivity


"The loss of muscle mass is a major contributor to disease-related deaths," said Andrew R. Judge, Ph.D., a researcher involved in the work from the Department of Physical Therapy at the University of Florida in Gainesville. "FoxO proteins may provide a target for therapies aimed at reducing muscle wasting and thus improving the quality of life and survival rates for patients with many different diseases."
To make this discovery, Judge and colleagues genetically inhibited the activity of "Forkhead boxO" proteins, or "FoxO," in the skeletal muscle of healthy control mice, septic mice, and mice with cancer. The loss of muscle mass in those with cancer and sepsis was significantly decreased by inhibition of FoxO activity. In healthy control animals inhibiting FoxO activity caused an increase in muscle cell size which occurred as a result of protein synthesis.
"No one can deny that the human body was meant to move, and to move often," said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal, "but the reality is that many of us don't move enough, whether because of disease, injury, or simply a busy schedule. This discovery is another important step towards the treatment of muscle wasting in cancer, severe infection or aging -- or to maintain our muscle mass to help face the slings and arrows of outrageous fortune."

[Lufega]

Any idea what inhibits this ?

[niner]

Any idea what inhibits this ?

Gene therapy... I don't know of any small molecules that interfere with these transcription factors, but in principle, you could put together an assay (probably not easy) and screen for compounds, the same way they did with telomerase/cycloastragenol (alters repressor binding, a sorta similar situation).

[CaptainFuture]

So after reading this we all had the same thought.

There seem to be 4 FOXOs in mammals so inhibiting one may not be enough. In addition to this I have no idea what the beneficial effects of FOXOs are. How can dFOXO overexpression increase lifespan in flies when inhibiting FOXOs in mice seems to do the opposite?

http://www.sciencema...82/361.abstract

We overexpressed dFOXO, a downstream effector of IIS, in the adult Drosophila fat body, which increased life-span and reduced fecundity of females

http://www.jimmunol....171/4/1623.full

Several reports have recently indicated that phosphorylation of FOXOs may be more complex and involve additional sites on these proteins. For example, the serum- and glucocorticoid-induced kinase (SGK) is also capable of inactivating FOXO3a (13). SGKs are closely related to PKB and their activation is also dependent upon PI3K-activity. Interestingly, SGK and PKB display differences with respect to the efficacy with which they phosphorylate the regulatory sites of FOXO3a. As the phosphorylation of each regulatory site of FOXO3a appears to be critical for the efficient exclusion from the nucleus (see below), it is likely that SGK and PKB cooperate in coordinately regulating FOXO transcription factors.
Recently, two further kinases have been identified that can phosphorylate FOXOs on additional sites. Phosphorylation by the dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A) decreases the ability of FOXO1 to stimulate transcription, and reduces the proportion in the nucleus (14). In addition, PKB-catalyzed phosphorylation of the residue equivalent to S2 in FOXO1 creates a recognition motif for casein kinase I (CK1), allowing it to phosphorylate S4 (Fig. 2). The phosphorylated S4 in turn "primes" the CK1 catalyzed phosphorylation of S5 (15).

EDIT: Vitamin D and FOXO

Mol Cell Biol. 2010 Oct;30(20):4890-900. Epub 2010 Aug 23

Stimulation of Sirt1-Regulated FoxO Protein Function by the Ligand-Bound
Vitamin D Receptor.
An BS, Tavera-Mendoza LE, Dimitrov V, Wang X, Calderon MR, Wang HJ,
White JH.
Department of Physiology, McIntyre Medical Sciences Bldg., Rm. 1112,
McGill University, 3655 Drummond St., Montreal, Quebec H3G1Y6, Canada.

Hormonal vitamin D, 1,25-dihydroxyvitamin D (1,25D), signals through the
nuclear vitamin D receptor (VDR). 1,25D regulates cell proliferation and
differentiation and has been identified as a cancer chemopreventive
agent. FoxO proteins are transcription factors that control cell
proliferation and survival. They function as tumor suppressors and are
associated with longevity in several organisms. Accumulating data have
revealed that 1,25D and FoxO proteins regulate similarly common target
genes. We show here that the ligand-bound VDR regulates the
posttranslational modification and function of FoxO proteins. 1,25D
treatment enhances binding of FoxO3a and FoxO4 within 4 h to promoters
of FoxO target genes and blocks mitogen-induced FoxO protein nuclear
export. The VDR associates directly with FoxO proteins and regulators,
the sirtuin 1 (Sirt1) class III histone deacetylase (HDAC), and protein
phosphatase 1. In addition, phosphatase activity and trichostatin
A-resistant HDAC activity coimmunoprecipitate with the VDR. 1,25D
treatment rapidly (in <4 h) induces FoxO deacetylation and
dephosphorylation, consistent with activation. In contrast, ablation of
VDR expression enhances FoxO3a phosphorylation, as does knockdown of
Sirt1, consistent with the coupling of FoxO acetylation and
phosphorylation. 1,25D regulation of common VDR/FoxO target genes is
attenuated by blockade of phosphatase activity or by small interfering
RNA (siRNA)-mediated knockdown of Sirt1 or FoxO protein expression.
Finally, 1,25D-dependent cell cycle arrest is blocked in
FoxO3a-deficient cells, indicating that FoxO proteins are key downstream
mediators of the antiproliferative actions of 1,25D. These studies link
1,25D signaling through the VDR directly to Sirt1 and FoxO function and
provide a molecular basis for the cancer chemopreventive actions of
1,25D.

PMID: 20733005

Edited by CaptainFuture, 02 March 2012 - 08:47 AM.

[CaptainFuture]

It seems that the effects of FOXOs are not that easy to pin down.

Aging Cell. 2011 Aug;10(4):622-8. doi: 10.1111/j.1474-9726.2011.00698.x. Epub 2011 Apr 12.

Candidate gene study of FOXO1, FOXO4, and FOXO6 reveals no association with human longevity in Germans.

Kleindorp R, Flachsbart F, Puca AA, Malovini A, Schreiber S, Nebel A.

Source

Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstrasse 12, Kiel, Germany.

Abstract

In mammals, the forkhead box class O (FOXO) family of transcription factors consists of the four members FOXO1, FOXO3A, FOXO4, and FOXO6. The FOXO genes are homologues of daf-16, a key regulator of the insulin-IGF1 signaling pathway and a modulator of lifespan in Caenorhabditis elegans. Recently, variants in FOXO3A have consistently been associated with human longevity in various populations worldwide. Given this confirmed finding, it is conceivable that polymorphisms in the other FOXO genes might have a similar effect on human longevity. To evaluate whether allelic variation in FOXO1, FOXO4, and FOXO6 influences the ability to become long-lived, we performed a comprehensive haplotype-tagging analysis of the three genes in a group of 1447 centenarians/nonagenarians and 1029 younger controls from Germany. This is the first investigation to analyze a possible association of human longevity with FOXO4 and FOXO6, respectively, and the largest and most comprehensive study to date to assess the genetic contribution of FOXO1 to the phenotype. Our results suggest that in Germans, none of the three genes plays a significant role in the ability to reach old age. With regard to FOXO1, this observation is supported by data from an Italian sample and is consistent with several previous reports, but appears to be in contrast to a recent study of Han Chinese. The discrepant association findings in Europeans and Chinese may be explained by their different FOXO1 linkage disequilibrium structures and could indicate a Chinese- or Asian-specific effect.
© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.