Disrupted autophagy undermines skeletal muscle adaptation and integrity

This review assesses the importance of proteostasis in skeletal muscle maintenance with a specific emphasis on autophagy. Skeletal muscle appears to be particularly vulnerable to genetic defects in basal and induced autophagy, indicating that autophagy is co-substantial to skeletal muscle maintenance and adaptation. We discuss emerging evidence that tension-induced protein unfolding may act as a direct link between mechanical stress and autophagic pathways. Mechanistic links between protein damage, autophagy and muscle hypertrophy, which is also induced by mechanical stress, are still poorly understood. However, some mouse models of muscle disease show ameliorated symptoms upon effective targeting of basal autophagy. These findings highlight the importance of autophagy as therapeutic target and suggest that elucidating connections between protein unfolding and mTOR-dependent or mTOR-independent hypertrophic responses is likely to reveal specific therapeutic windows for the treatment of muscle wasting disorders

Genome-wide identification of FoxO-dependent gene networks in skeletal muscle during C26 cancer cachexia

BACKGROUND: Evidence from cachectic cancer patients and animal models of cancer cachexia supports the involvement of Forkhead box O (FoxO) transcription factors in driving cancer-induced skeletal muscle wasting. However, the genome-wide gene networks and associated biological processes regulated by FoxO during cancer cachexia are unknown. We hypothesize that FoxO is a central upstream regulator of diverse gene networks in skeletal muscle during cancer that may act coordinately to promote the wasting phenotype. METHODS: To inhibit endogenous FoxO DNA-binding, we transduced limb and diaphragm muscles of mice with AAV9 containing the cDNA for a dominant negative (d.n.) FoxO protein (or GFP control). The d.n.FoxO construct consists of only the FoxO3a DNA-binding domain that is highly homologous to that of FoxO1 and FoxO4, and which outcompetes and blocks endogenous FoxO DNA binding. Mice were subsequently inoculated with Colon-26 (C26) cells and muscles harvested 26 days later. RESULTS: Blocking FoxO prevented C26-induced muscle fiber atrophy of both locomotor muscles and the diaphragm and significantly spared force deficits. This sparing of muscle size and function was associated with the differential regulation of 543 transcripts (out of 2,093) which changed in response to C26. Bioinformatics analysis of upregulated gene transcripts that required FoxO revealed enrichment of the proteasome, AP-1 and IL-6 pathways, and included several atrophy-related transcription factors, including Stat3, Fos, and Cebpb. FoxO was also necessary for the cancer-induced downregulation of several gene transcripts that were enriched for extracellular matrix and sarcomere protein-encoding genes. We validated these findings in limb muscles and the diaphragm through qRT-PCR, and further demonstrate that FoxO1 and/or FoxO3a are sufficient to increase Stat3, Fos, Cebpb, and the C/EBPβ target gene, Ubr2. Analysis of the Cebpb proximal promoter revealed two bona fide FoxO binding elements, which we further establish are necessary for Cebpb promoter activation in response to IL-6, a predominant cytokine in the C26 cancer model. CONCLUSIONS: These findings provide new evidence that FoxO-dependent transcription is a central node controlling diverse gene networks in skeletal muscle during cancer cachexia, and identifies novel candidate genes and networks for further investigation as causative factors in cancer-induced wasting.R01 AR060217 - NIAMS NIH HHS; R01 AR060209 - NIAMS NIH HHS; T32 HD043730 - NICHD NIH HHS; R00 HL098453 - NHLBI NIH HHS; R00HL098453 - NHLBI NIH HHS; R01AR060209 - NIAMS NIH HHS; R01AR060217 - NIAMS NIH HH

Alternative medicine and herbal remedies in the treatment of erectile dysfunction: A systematic review

Objectives: To systematically review and discuss the current evidence from placebo-controlled clinical trials that investigated the use of alternative medicines and herbal remedies in the management of erectile dysfunction (ED). Methods: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)- based systematic review using specific keyword combinations was conducted on the PubMed and Scopus databases. Randomised controlled trials investigating herbal medicine in at least one group and using the International Index of Erectile Function (IIEF) as an outcome in patients primarily diagnosed with ED were included for review. Results: Following the literature search, screening and eligibility analysis, a total of 42 articles were included. The 42 articles were categorised as single herb extractions (n = 14), combination herbal formula (n = 5), combination of herbal formula and non-herbal nutraceuticals (n = 7), non-herbal nutraceuticals (n = 5), acupuncture and moxibustion (n = 2), diet and nutrition (n = 3), exercise (n = 5), and topical treatments (n = 1). Based on the results, Korean ginseng, Pygnogenol and Prelox, Tribulus terrestris, Lepidium meyenii, L-arginine, acupuncture and lifestyle interventions were the more predominantly investigated treatments interventions for ED. Conclusions: Panax ginseng, Pygnogenol, Prelox and Tribulus terrestris have promising evidence as herbal products, alongside L-arginine as a nutritional supplement, for ED based on IIEF outcomes, and warrant further clinical investigation. The mechanisms of action remain unclear, but each of these appears to in part increase nitric oxide synthesis. Importantly, improved diet and exercise should be considered, particularly in patients with obesity or diabetes mellitus

Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: The pilot phase of a randomised controlled trial

Summary: Background Preoperative (neoadjuvant) chemotherapy and radiotherapy are more eff ective than similar postoperative treatment for oesophageal, gastric, and rectal cancers, perhaps because of more eff ective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery. The FOxTROT trial aims to investigate the feasibility, safety, and effi cacy of preoperative chemotherapy for colon cancer. Methods In the pilot stage of this randomised controlled trial, 150 patients with radiologically staged locally advanced (T3 with ≥5 mm invasion beyond the muscularis propria or T4) tumours from 35 UK centres were randomly assigned (2:1) to preoperative (three cycles of OxMdG [oxaliplatin 85 mg/m², l-folinic acid 175 mg, fl uorouracil 400 mg/m² bolus, then 2400 mg/m² by 46 h infusion] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG) or standard postoperative chemotherapy (12 cycles of OxMdG). Patients with KRAS wild-type tumours were randomly assigned (1:1) to receive panitumumab (6 mg/kg; every 2 weeks with the fi rst 6 weeks of chemotherapy) or not. Treatment allocation was through a central randomisation service using a minimised randomisation procedure including age, radiological T and N stage, site of tumour, and presence of defunctioning colostomy as stratifi cation variables. Primary outcome measures of the pilot phase were feasibility, safety, and tolerance of preoperative therapy, and accuracy of radiological staging. Analysis was by intention to treat. This trial is registered, number ISRCTN 87163246. Findings 96% (95 of 99) of patients started and 89% (85 of 95) completed preoperative chemotherapy with grade 3–4 gastrointestinal toxicity in 7% (seven of 94) of patients. All 99 tumours in the preoperative group were resected, with no signifi cant diff erences in postoperative morbidity between the preoperative and control groups: 14% (14 of 99) versus 12% (six of 51) had complications prolonging hospital stay (p=0·81). 98% (50 of 51) of postoperative chemotherapy patients had T3 or more advanced tumours confi rmed at post-resection pathology compared with 91% (90 of 99) of patients following preoperative chemotherapy (p=0·10). Preoperative therapy resulted in signifi cant downstaging of TNM5 compared with the postoperative group (p=0·04), including two pathological complete responses, apical node involvement (1% [one of 98] vs 20% [ten of 50], p<0·0001), resection margin involvement (4% [ four of 99] vs 20% [ten of 50], p=0·002), and blinded centrally scored tumour regression grading: 31% (29 of 94) vs 2% (one of 46) moderate or greater regression (p=0·0001). Interpretation Preoperative chemotherapy for radiologically staged, locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity. Proceeding to the phase 3 trial, to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome, is appropriate

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes