Browsing by Subject "Cachexia"
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Item Open Access A Toolbox for Observing and Modulating the Gut-Brain Axis(2022) Garrett, Aliesha DanielleAn estimated 10% of people worldwide have an enteric nervous system (ENS) related illness including irritable bowel syndrome (IBS), diabetes, colorectal cancer, fecal incontinence, and chronic constipation or diarrhea. Current drug treatments have severe side effects and often do not adequately address symptoms; a new approach is needed. ENS stimulation is a promising therapy for these patients, but a major limitation to this approach is our lack of knowledge. The human ENS is comprised of 5 million neurons and drives the digestive system, but its normal function and connections to the central nervous system (CNS) remain poorly understood. One of the major canonical signaling pathways between the ENS and the CNS is the vagus nerve, but the neural circuits involved are still under investigation. Better understanding of these circuits would provide a potential method of treatment for ENS related illness, with neurostimulation serving as an alternative to pharmaceutical treatments. Herein I describe a project which addresses these needs via development of new imaging tools to better understand the gut-brain axis, as well as demonstrating its utility as a target for treatment of gastrointestinal (GI) illness, specifically cancer-associated cachexia. Leaders in enteric neuroscience note that the continued inconsistencies in GI electrotherapies are driven by a fundamental lack of understanding of gut innervation and circuitry. New tools to directly observe colonic innervation and neuronal response, as well as a map of the whole peripheral nervous system, will reveal crucial targets for stimulation and enable more efficient targeting selection for neurostimulation or other local interventions, which will reduce off target effects and improve efficacy. To address these issues, I have developed an intravital window for direct imaging of the colon, enabling observation of colonic ENS response to stimulation in vivo for the first time. Additionally, I have developed an embryonic window, allowing visualization of embryonic GI development from E9.5 through birth. Finally, I have generated a mouse peripheral nerve map based on Diffusion Tensor Magnetic Resonance Imaging (DT MRI). Using novel scan parameters and post-processing algorithms, I identified nerve fibers throughout the body and generated quantitative tractography which specifically highlights GI innervation via the vagus nerve. Cachexia is a multi-systemic syndrome which produces weight loss, muscle atrophy, adipose wasting, fatigue, and anorexia. Affecting an estimated 1% of the global population and up to 80% of all cancer patients, cachexia is fatal in roughly 30% of cases and is incurable. Cancer-associated cachexia (CAC) is particularly devastating as in addition to resulting in decreased quality of life, CAC reduces tolerance and efficacy of cancer treatments and higher overall mortality. As many as half of all cancer deaths are attributed to CAC. There are currently no clinically meaningful treatments for CAC, despite attempts to employ dietary support, physical therapy, anti-inflammatory medication, appetite stimulants, and other supportive therapies. Herein I describe potential therapeutic approach for treatment of CAC via vagal perturbation – either by vagotomy or ultra-low frequency vagal block with an implanted stimulator. This intervention significantly attenuates weight loss, skeletal muscle atrophy, anorexia, urea cycle dysregulation, and circulating inflammatory cytokine elevation. Most importantly, it increases survival time in mice injected with tumor cells, suggesting this could be a clinically meaningful approach for treatment of CAC.
Item Open Access Fiber type-specific nitric oxide protects oxidative myofibers against cachectic stimuli.(PLoS One, 2008-05-07) Yu, Zengli; Li, Ping; Zhang, Mei; Hannink, Mark; Stamler, Jonathan S; Yan, ZhenOxidative skeletal muscles are more resistant than glycolytic muscles to cachexia caused by chronic heart failure and other chronic diseases. The molecular mechanism for the protection associated with oxidative phenotype remains elusive. We hypothesized that differences in reactive oxygen species (ROS) and nitric oxide (NO) determine the fiber type susceptibility. Here, we show that intraperitoneal injection of endotoxin (lipopolysaccharide, LPS) in mice resulted in higher level of ROS and greater expression of muscle-specific E3 ubiqitin ligases, muscle atrophy F-box (MAFbx)/atrogin-1 and muscle RING finger-1 (MuRF1), in glycolytic white vastus lateralis muscle than in oxidative soleus muscle. By contrast, NO production, inducible NO synthase (iNos) and antioxidant gene expression were greatly enhanced in oxidative, but not in glycolytic muscles, suggesting that NO mediates protection against muscle wasting. NO donors enhanced iNos and antioxidant gene expression and blocked cytokine/endotoxin-induced MAFbx/atrogin-1 expression in cultured myoblasts and in skeletal muscle in vivo. Our studies reveal a novel protective mechanism in oxidative myofibers mediated by enhanced iNos and antioxidant gene expression and suggest a significant value of enhanced NO signaling as a new therapeutic strategy for cachexia.Item Open Access Sarcopenia: A Time for Action. An SCWD Position Paper.(Journal of cachexia, sarcopenia and muscle, 2019-10) Bauer, Juergen; Morley, John E; Schols, Annemie MWJ; Ferrucci, Luigi; Cruz-Jentoft, Alfonso J; Dent, Elsa; Baracos, Vickie E; Crawford, Jeffrey A; Doehner, Wolfram; Heymsfield, Steven B; Jatoi, Aminah; Kalantar-Zadeh, Kamyar; Lainscak, Mitja; Landi, Francesco; Laviano, Alessandro; Mancuso, Michelangelo; Muscaritoli, Maurizio; Prado, Carla M; Strasser, Florian; von Haehling, Stephan; Coats, Andrew JS; Anker, Stefan DThe term sarcopenia was introduced in 1988. The original definition was a "muscle loss" of the appendicular muscle mass in the older people as measured by dual energy x-ray absorptiometry (DXA). In 2010, the definition was altered to be low muscle mass together with low muscle function and this was agreed upon as reported in a number of consensus papers. The Society of Sarcopenia, Cachexia and Wasting Disorders supports the recommendations of more recent consensus conferences, i.e. that rapid screening, such as with the SARC-F questionnaire, should be utilized with a formal diagnosis being made by measuring grip strength or chair stand together with DXA estimation of appendicular muscle mass (indexed for height2). Assessments of the utility of ultrasound and creatine dilution techniques are ongoing. Use of ultrasound may not be easily reproducible. Primary sarcopenia is aging associated (mediated) loss of muscle mass. Secondary sarcopenia (or disease-related sarcopenia) has predominantly focused on loss of muscle mass without the emphasis on muscle function. Diseases that can cause muscle wasting (i.e. secondary sarcopenia) include malignant cancer, COPD, heart failure, and renal failure and others. Management of sarcopenia should consist of resistance exercise in combination with a protein intake of 1 to 1.5 g/kg/day. There is insufficient evidence that vitamin D and anabolic steroids are beneficial. These recommendations apply to both primary (age-related) sarcopenia and secondary (disease related) sarcopenia. Secondary sarcopenia also needs appropriate treatment of the underlying disease. It is important that primary care health professionals become aware of and make the diagnosis of age-related and disease-related sarcopenia. It is important to address the risk factors for sarcopenia, particularly low physical activity and sedentary behavior in the general population, using a life-long approach. There is a need for more clinical research into the appropriate measurement for muscle mass and the management of sarcopenia. Accordingly, this position statement provides recommendations on the management of sarcopenia and how to progress the knowledge and recognition of sarcopenia.