dStarvation, like many other catabolic conditions, induces loss of skeletal muscle mass by promoting fiber atrophy. In addition to the canonical processes, the starvation-induced response employs many distinct pathways that make it a unique atrophic program. However, in the multiplex of the underlying mechanisms, several components of starvation-induced atrophy have yet to be fully understood and their roles and interplay remain to be elucidated. Here we unveiled the role of tumor necrosis factor receptor-associated factor 6 (TRAF6), a unique E3 ubiquitin ligase and adaptor protein, in starvation-induced muscle atrophy. Targeted ablation of TRAF6 suppresses the expression of key regulators of atrophy, including MAFBx, MuRF1, p62, LC3B, Beclin1, Atg12, and Fn14. Ablation of TRAF6 also improved the phosphorylation of Akt and FoxO3a and inhibited the activation of 5= AMP-activated protein kinase in skeletal muscle in response to starvation. In addition, our study provides the first evidence of the involvement of endoplasmic reticulum stress and unfolding protein response pathways in starvation-induced muscle atrophy and its regulation through TRAF6. Finally, our results also identify lysine 63-linked autoubiquitination of TRAF6 as a process essential for its regulatory role in starvation-induced muscle atrophy.
Radiochromic film (RCF) is attractive as a thin, high resolution, 2D planar dosimeter. We have studied the uniformity, linearity, and reproducibility of a commercially supplied RCF system (model MD-55). Forty 12 cm long strips of RCF were exposed to uniform doses of 6 MV x rays. Optical density (OD) distributions were measured by a helium-neon scanning laser (633 nm) 2D densitometer and also with a manual densitometer. All film strips showed 8%-15% variations in OD values independent of densitometry technique which are evidently due to nonuniform dispersal of the sensor medium. A double exposure technique was developed to solve this problem. The film is first exposed to a uniform beam, which defines a pixel-by-pixel nonuniformity correction matrix. The film is then exposed to the unknown dose distribution, rescanned, and the net OD at each pixel corrected for nonuniformity. The double exposure technique reduces OD/unit dose variation to a 2%-5% random fluctuation. RCF response was found to deviate significantly from linearity at low doses (40% change in net OD/Gy from 1 to 30 Gy); a finding not previously reported. To study the tradeoff between statistical noise and spatial resolution, OD was averaged over blocks of adjacent 50 microns pixels (ranging from 1 x 1 to 10 x 10 pixels). Reproducibility, defined as the standard deviation of repeated single-pixel measurements on separate film pieces, was 2% at 30 Gy for a resolution of 0.25 mm. With careful correction for nonlinearity and nonuniformity, RCF is a promising quantitative 2D dosimeter for radiation oncology applications.
Radiation therapy dose escalation using stereotactic body radiation therapy may significantly improve both local control (LC) and overall survival (OS) for patients with inoperable pancreas cancer. However, ablative dose cannot be routinely offered because of the risk of causing severe injury to adjacent normal organs. Stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) represents a novel technique that may achieve safe delivery of ablative dose and improve long-term outcomes. Methods and Materials: We performed a single institution retrospective analysis of 35 consecutive pancreatic cancer patients treated with SMART in mid-inspiration breath hold on an MR-linear accelerator. Most had locally advanced disease (80%) and received induction chemotherapy (91.4%) for a median 3.9 months before stereotactic body radiation therapy. All were prescribed 5 fractions delivered in consecutive days to a median total dose of 50 Gy (BED 10 100 Gy 10), typically with a 120% to 130% hotspot. Elective nodal irradiation was delivered to 20 (57.1%) patients. No patient had fiducial markers placed and all were treated with continuous intrafraction MR visualization and automatic beam triggering. Results: With median follow-up of 10.3 months from SMART, acute (2.9%) and late (2.9%) grade 3 toxicities were uncommon. Oneyear LC, distant metastasis-free survival, progression-free survival, cause-specific survival, and OS were 87.8%, 63.1%, 52.4%, 77.6%, and 58.9%, respectively.
BACKGROUND & AIMS Acute pancreatitis (AP) and chronic pancreatitis (CP) share etiologies, but AP can be more severe and has higher mortality. We investigated features of CP that protect against severity. The amount of intra-pancreatic fat (IPF) is increased in obesity and fibrosis is increased in CP; so we studied whether fibrosis or fat regulate severity of AP attacks in patients with CP. METHODS We reviewed records from the University of Pittsburg Medical Center Autopsy database (1998–2008) for patients with diagnosed AP (n=23), CP (n=35), or both (AP-on-CP; n=15). Pancreatic histology samples from these patients and 50 randomly selected Controls (no pancreatic disease) were analyzed, and IPF data were correlated with computed tomography data. An adipocyte and acinar cell transwell co-culture system, with or without collagen Type-I (collagen-I), was used to study the effects of fibrosis on acinar-adipocyte interactions. We studied the effects of non-esterified fatty acids (NEFA) and adipokines on acinar cells in culture. RESULTS Levels of IPF were significantly higher among non-obese patients with CP than non-obese Controls. In CP or AP-on-CP, areas of IPF were surrounded by significantly more fibrosis than in Controls or patients with AP. Fat necrosis (FN)-associated peri-fat acinar necrosis (PFAN, indicated by NEFA spillage) contributed to most of the necrosis observed in AP samples; however, PFAN and total necrosis were significantly lower in samples from patients with CP and AP-on-CP. Fibrosis appeared to wall off the FN and limit PFAN, reducing acinar necrosis. In vitro, collagen-I limited the lipolytic flux between acinar cells and adipocytes and prevented increases in adipokines in the acinar compartment. This was associated with reduced acinar cell necrosis. However, NEFA, but not adipokines, caused acinar-cell necrosis. CONCLUSIONS Based on analysis of pancreatic samples from patients with CP, AP and AP-on-CP, and in vitro studies, fibrosis reduces the severity of acute exacerbations of CP by reducing lipolytic flux between adipocytes and acinar cells.
Skeletal muscle wasting attributed to inactivity has significant adverse functional consequences. Accumulating evidence suggests that peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and TNF-like weak inducer of apoptosis (TWEAK)-Fn14 system are key regulators of skeletal muscle mass in various catabolic states. While the activation of TWEAK-Fn14 signaling causes muscle wasting, PGC-1α preserves muscle mass in several conditions, including functional denervation and aging. However, it remains unknown whether there is any regulatory interaction between PGC-1α and TWEAK-Fn14 system during muscle atrophy. Here we demonstrate that TWEAK significantly reduces the levels of PGC-1α and mitochondrial content (∼50%) in skeletal muscle. Levels of PGC-1α are significantly increased in skeletal muscle of TWEAK-knockout (KO) and Fn14-KO mice compared to wild-type mice on denervation. Transgenic (Tg) overexpression of PGC-1α inhibited progressive muscle wasting in TWEAK-Tg mice. PGC-1α inhibited the TWEAK-induced activation of NF-κB (∼50%) and dramatically reduced (∼90%) the expression of atrogenes such as MAFbx and MuRF1. Intriguingly, muscle-specific overexpression of PGC-1α also prevented the inducible expression of Fn14 in denervated skeletal muscle. Collectively, our study demonstrates that TWEAK induces muscle atrophy through repressing the levels of PGC-1α. Overexpression of PGC-1α not only blocks the TWEAK-induced atrophy program but also diminishes the expression of Fn14 in denervated skeletal muscle.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.