Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.

Origin and Physiological Roles of Inflammation

Skeletal muscle mass increases during postnatal development through a process of hypertrophy, i.e. enlargement of individual muscle fibers, and a similar process may be induced in adult skeletal muscle in response to contractile activity, such as strength exercise, and specific hormones, such as androgens and β-adrenergic agonists. Muscle hypertrophy occurs when the overall rates of protein synthesis exceed the rates of protein degradation. Two major signaling pathways control protein synthesis, the IGF1-Akt-mTOR pathway, acting as a positive regulator, and the myostatin-Smad2/3 pathway, acting as a negative regulator, and additional pathways have recently been identified. Proliferation and fusion of satellite cells, leading to an increase in the number of myonuclei, may also contribute to muscle growth during early but not late stages of postnatal development and in some forms of muscle hypertrophy in the adult. Muscle atrophy occurs when protein degradation rates exceed protein synthesis, and may be induced in adult skeletal muscle in a variety of conditions, including starvation, denervation, cancer cachexia, heart failure and aging. Two major protein degradation pathways, the proteasomal and the autophagic-lysosomal pathways, are activated during muscle atrophy and variably contribute to the loss of muscle mass. These pathways involve a variety of atrophy-related genes or atrogenes, which are controlled by specific transcription factors, such as FoxO3, which is negatively regulated by Akt, and NF-κB, which is activated by inflammatory cytokines.

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/febs.12253

Mechanisms regulating skeletal muscle growth and atrophy

Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases.

Cellular and molecular mechanisms of muscle atrophy

Metabolism generates oxygen radicals, which contribute to oncogenic mutations. Activated oncogenes and loss of tumor suppressors in turn alter metabolism and induce aerobic glycolysis. Aerobic glycolysis or the Warburg effect links the high rate of glucose fermentation to cancer. Together with glutamine, glucose via glycolysis provides the carbon skeletons, NADPH, and ATP to build new cancer cells, which persist in hypoxia that in turn rewires metabolic pathways for cell growth and survival. Excessive caloric intake is associated with an increased risk for cancers, while caloric restriction is protective, perhaps through clearance of mitochondria or mitophagy, thereby reducing oxidative stress. Hence, the links between metabolism and cancer are multifaceted, spanning from the low incidence of cancer in large mammals with low specific metabolic rates to altered cancer cell metabolism resulting from mutated enzymes or cancer genes.

/pdf/links-between-metabolism-and-cancer-1pg3h9gox2.pdf

Links between metabolism and cancer

Sirtuin 3 (SIRT3) is a member of the sirtuin family of proteins that promote longevity in many organisms. Increased expression of SIRT3 has been linked to an extended life span in humans. Here, we have shown that Sirt3 protects the mouse heart by blocking the cardiac hypertrophic response. Although Sirt3-deficient mice appeared to have normal activity, they showed signs of cardiac hypertrophy and interstitial fibrosis at 8 weeks of age. Application of hypertrophic stimuli to these mice produced a severe cardiac hypertrophic response, whereas Sirt3-expressing Tg mice were protected from similar stimuli. In primary cultures of cardiomyocytes, Sirt3 blocked cardiac hypertrophy by activating the forkhead box O3a-dependent (Foxo3a-dependent), antioxidant-encoding genes manganese superoxide dismutase (MnSOD) and catalase (Cat), thereby decreasing cellular levels of ROS. Reduced ROS levels suppressed Ras activation and downstream signaling through the MAPK/ERK and PI3K/Akt pathways. This resulted in repressed activity of transcription factors, specifically GATA4 and NFAT, and translation factors, specifically eukaryotic initiation factor 4E (elf4E) and S6 ribosomal protein (S6P), which are involved in the development of cardiac hypertrophy. These results demonstrate that SIRT3 is an endogenous negative regulator of cardiac hypertrophy, which protects hearts by suppressing cellular levels of ROS.

/pdf/sirt3-blocks-the-cardiac-hypertrophic-response-by-augmenting-1ohl7ocxom.pdf

Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice

Forkhead box O (FoxO) transcription factors FoxO1, FoxO3a, FoxO4 and FoxO6, the mammalian orthologs of Caenorhabditis elegans DAF-16, are emerging as an important family of proteins that modulate the expression of genes involved in apoptosis, the cell cycle, DNA damage repair, oxidative stress, cell differentiation, glucose metabolism and other cellular functions. FoxO proteins are regulated by multiple mechanisms. They undergo inhibitory phosphorylation by protein kinases such as Akt, SGK, IKK and CDK2 in response to external and internal stimuli. By contrast, they are activated by upstream regulators such as JNK and MST1 under stress conditions. Their activities are counterbalanced by the acetylases CBP and p300 and the deacetylase SIRT1. Also, whereas polyubiquitylation of FoxO1 and FoxO3a leads to their degradation by the proteasome, monoubiquitylation of FoxO4 facilitates its nuclear localization and augments its transcriptional activity. Thus, the potent functions of FoxO proteins are tightly controlled by complex signaling pathways under physiological conditions; dysregulation of these proteins may ultimately lead to disease such as cancer.

Dynamic FoxO transcription factors

It has been well established that cyclin-dependent kinases (CDKs) including CDK2 and CDK1 play an essential role in mediating cell-cycle arrest, DNA repair and apoptosis in cells with damaged genomes. Following DNA damage, the function of CDKs is inhibited, and therefore cells are arrested at the G(1), S or G(2)/M phase of the cell-division cycle. It is believed that DNA damage-induced cell cycle arrest is important, because it allows cells to either repair the damage and survive or commit to apoptotic cell death. However, the molecular bases for the two cell fate options are not fully understood. Recently, we provided evidence that CDK2 interacts with and phosphorylates the forkhead transcription factor FOXO1. Importantly, activated CDK2 inhibits the pro-apoptotic function of FOXO1. However, in the presence of high levels of double-strand breaks (DSBs) the CDK2-mediated inhibition of FOXO1 is abrogated due to the ablation of CDK2 activity, and therefore the anti-apoptotic function of FOXO1 is restored. Thus, CDK2 silencing-dependent activation of FOXO1 represents a new mechanism that links DNA strand breakage to cell death.

CDK2 and FOXO1 : A fork in the road for cell fate decisions

BACKGROUND

Androgens control homeostasis of the normal prostate and growth of prostate cancer (PCa) through the androgen receptor (AR) by regulating gene networks involving in cell proliferation, differentiation, and survival. We demonstrated previously that expression of Skp2, a key protein regulating cell entry into the S phase, is inhibited by androgens in an AR-dependent manner (Oncogene, 2004; 23(12): 2161–2176). However, the underlying mechanism of this regulation is unknown.



METHODS

Using the LNCaP PCa cell line as a working model, the effect of androgens on the expression of Skp2 was examined by Western and Northern blot analyses. Cell cycle was measured by fluorescence-activated cell sorting (FACS). Gene transfection was performed by electroporation to manipulate the expression levels of proteins studied.



RESULTS

At physiological levels androgens markedly repressed Skp2 expression but slightly induced Skp2 expression at subphysiological levels. Androgens modestly decreased the stability of the Skp2 protein. Androgenic repression of Skp2 expression was completely abolished by E1A-mediated inactivation of pocket proteins including RB, p130, and p107. Moreover, ectopic expression of p107 inhibited Skp2 expression, and silencing of p107 partially blocked androgenic repression of Skp2.



CONCLUSIONS

Our data indicate that androgens repress Skp2 expression via p107-dependent and -independent pathways in PCa cells. These regulatory mechanisms may be targeted for the development of new therapeutics of androgen-refractory PCa. Prostate 72:225–232, 2012. © 2011 Wiley Periodicals, Inc.

/pdf/androgens-repress-expression-of-the-f-box-protein-skp2-via-1w91e31shs.pdf

Haojie Huang

Papers

Dynamic FoxO transcription factors

CDK2 and FOXO1 : A fork in the road for cell fate decisions

Androgens repress expression of the f‐box protein Skp2 via p107 dependent and independent mechanisms in LNCaP prostate cancer cells