Resveratrol prevents dexamethasone-induced expression of the muscle atrophy-related ubiquitin ligases atrogin-1 and MuRF1 in cultured myotubes through a SIRT1-dependent mechanism.

Resveratrol (3,5,4'-trihydroxystilbene) has been ascribed multiple beneficial biological effects but the influence of resveratrol on glucocorticoid-induced muscle atrophy is not known. We examined the effects of resveratrol on dexamethasone-induced atrogin-1 and MuRF1 expression, FOXO1 acetylation, protein degradation and atrophy in cultured L6 myotubes. In addition, the role of the deacetylase SIRT1 in the effects of resveratrol was determined by transfecting myotubes with SIRT1 siRNA. The catabolic effects of dexamethasone were prevented by resveratrol and the protective effects of resveratrol on dexamethasone-induced atrogin-1 and MuRF1 expression were abolished in myotubes transfected with SIRT1 siRNA. Results suggest that resveratrol can prevent glucocorticoid-induced muscle wasting and that this effect is at least in part SIRT1-dependent.

Ileostomy pathway virtually eliminates readmissions for dehydration in new ostomates.

BACKGROUND: New ileostomates face significant physical and psychological adaptations. Despite advanced resources, such as wound, ostomy, and continence nurses, we observed a high readmission rate for dehydration among patients with new ileostomies. OBJECTIVE: Our goal was to create a pathway to reduce readmission and facilitate patient education and well-being. DESIGN: The 'Ileostomy Pathway' was established by a collaborative group at Beth Israel Deaconess Medical Center. A standardized set of patient education tools was developed to be used throughout the perioperative process. Patient's education started with the preoperative visit. All patients were directly engaged in ostomy management and trained in a stepwise progression. Patients were discharged from the hospital with flow sheets, supplies for recording intake/output, and visiting nurse services. Prospectively collected data from the first 7 months was compared with a retrospective database of the previous 4 years. SETTINGS: This study was conducted at a tertiary academic center. PATIENTS: Patients with a new permanent or temporary ileostomy were included. INTERVENTIONS: A new ileostomy pathway was created. MAIN OUTCOME MEASURES: The primary outcome measured was readmission rates. RESULTS: One hundred sixty-one patients were assigned to prepathway implementation and 42 were assigned to postpathway implementation. One hundred three of 203 (50.7%) patients were men, and 58 of 203 (28.6%) patients had permanent ostomies. Overall readmission rate was 35.4% and 21.4% for the prepathway and postpathway groups. The readmission rate for dehydration was 15.5% (25/161) for prepathway patients, but dropped to 0% in the study group. The average length of stay after creation of the new ostomy was 7.5 days and 6.6 days for prepathway and postpathway groups. LIMITATIONS: This study was limited by its small sample size and the lack of randomization. CONCLUSIONS: A simple, educational program for new ileostomy patients that includes preoperative teaching, standardized teaching materials, in-hospital engagement, observed management, and postdischarge tracking of intake and output is very effective in decreasing hospital readmission. The average length of stay remained stable, despite the addition of this teaching program to our perioperative/inpatient care.

C/EBPß regulates dexamethasone-induced muscle cell atrophy and expression of atrogin-1 and MuRF1.

Muscle wasting in catabolic patients is in part mediated by glucocorticoids and is associated with increased expression and activity of the transcription factor C/EBPß. It is not known, however, if C/EBPß is causally linked to glucocorticoid-induced muscle atrophy. We used dexamethasone-treated L6 myoblasts and myotubes to test the role of C/EBPß in glucocorticoid-induced expression of the muscle-specific ubiquitin ligases atrogin-1 and MuRF1, protein degradation, and muscle atrophy by transfecting cells with C/EBPß siRNA. In myoblasts, silencing C/EBPß expression with siRNA inhibited dexamethasone-induced increase in protein degradation, atrogin-1 and MuRF1 expression, and muscle cell atrophy. Similar effects of C/EBPß siRNA were seen in myotubes except that the dexamethasone-induced increase in MuRF1 expression was not affected by C/EBPß siRNA in myotubes. In additional experiments, overexpressing C/EBPß did not influence atrogin-1 or MuRF1 expression in myoblasts or myotubes. Taken together, our observations suggest that glucocorticoid-induced muscle wasting is at least in part regulated by C/EBPß. Increased C/EBPß expression alone, however, is not sufficient to upregulate atrogin-1 and MuRF1 expression.

Sepsis and glucocorticoids downregulate the expression of the nuclear cofactor PGC-1beta in skeletal muscle.

Muscle wasting during sepsis is at least in part regulated by glucocorticoids and is associated with increased transcription of genes encoding the ubiquitin ligases atrogin-1 and muscle-specific RING-finger protein-1 (MuRF1). Recent studies suggest that muscle atrophy caused by denervation is associated with reduced expression of the nuclear cofactor peroxisome proliferator-activated receptor-γ coactivator (PGC)-1ß and that PGC-1ß may be a repressor of the atrogin-1 and MuRF1 genes. The influence of other muscle-wasting conditions on the expression of PGC-1ß is not known. We tested the influence of sepsis and glucocorticoids on PGC-1ß and examined the potential link between downregulated PGC-1ß expression and upregulated atrogin-1 and MuRF1 expression in skeletal muscle. Sepsis in rats and mice and treatment with dexamethasone resulted in downregulated expression of PGC-1ß and increased expression of atrogin-1 and MuRF1 in the fast-twitch extensor digitorum longus muscle, with less pronounced changes in the slow-twitch soleus muscle. In additional experiments, adenoviral gene transfer of PGC-1ß into cultured C2C12 myotubes resulted in a dose-dependent decrease in atrogin-1 and MuRF1 mRNA levels. Treatment of cultured C2C12 myotubes with dexamethasone or PGC-1ß small interfering RNA (siRNA) resulted in downregulated PGC-1ß expression and increased protein degradation. Taken together, our results suggest that sepsis- and glucocorticoid-induced muscle wasting may, at least in part, be regulated by decreased expression of the nuclear cofactor PGC-1ß.

Corticosteroids and muscle wasting: role of transcription factors, nuclear cofactors, and hyperacetylation.

PURPOSE OF REVIEW: The purpose of this review is to discuss novel insight into mechanisms of glucocorticoid-regulated muscle wasting, in particular the role of transcription factors and nuclear cofactors. In addition, novel strategies that may become useful in the treatment or prevention of glucocorticoid-induced muscle wasting are reviewed. RECENT FINDINGS: Studies suggest that glucocorticoid-induced upregulation of the transcription factors Forkhead box O 1 and CCAAT/enhancer-binding protein beta and downregulation of MyoD and myogenin are involved in glucocorticoid-induced muscle wasting. In addition, glucocorticoid-induced hyperacetylation caused by increased expression of the nuclear cofactor p300 and its histone acetyl transferase activity and decreased expression and activity of histone deacetylases plays an important role in glucocorticoid-induced muscle proteolysis and wasting. Other mechanisms may also be involved in glucocorticoid-induced muscle wasting, including insulin resistance and store-operated calcium entry. Novel potential strategies to prevent or treat glucocorticoid-induced muscle wasting include the use of small molecule histone deacetylase activators, dissociated glucocorticoid receptor agonists, and 11beta-hydroxysteroid dehydrogenase type 1 inhibitors. SUMMARY: An increased understanding of molecular mechanisms regulating glucocorticoid-induced muscle wasting will help develop new strategies to prevent and treat this debilitating condition.

Primary Leiomyosarcoma of the Colon: A Report of Two Cases, Review of the Literature, and Association with Immunosuppression for IBD and Rheumatoid Arthritis.

Primary leiomyosarcomas (LMS) of the colon are rare and aggressive neoplasms and have been infrequently reported in the literature. These tumors are more aggressive and have poorer prognoses than adenocarcinoma of the colon and are often mistaken as such on initial evaluation. While the former has a clear association with inflammatory bowel disease (IBD), this correlation is not known to exist with LMS and IBD. Nor is there a known link between LMS and the immunosuppression for IBD, despite the known association between malignancy and immunosuppression for other diseases. Due to the low prevalence of this disease entity, there is limited knowledge and literature on the approach to diagnosing and treating these neoplasms, especially in the setting of the aforementioned comorbidities. Here, we describe two cases of this rare entity, presenting in two different circumstances: one in the setting of immunosuppression for IBD and arthritis, with a synchronous urothelial carcinoma, and the second appearing as the source of an acute abdomen. Both diagnoses were established following pathologic analysis.