Periodic Reporting for period 1 - LiSDMA (Liver steatosis drives muscle atrophy in type 2 diabetes patients.)
Reporting period: 2018-02-21 to 2020-02-20
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and encompasses a histological spectrum of liver diseases. It starts with a fatty liver (also called hepatic steatosis) and can progress to more severe stages which include the appearance of inflammation and scarring. A fatty liver is highly prevalent and is found in ~25% of all adults, in up to ~70% of adults who are overweight, and in >90% of the individuals who are morbidly obese, indicating a close link with obesity. It is well known that the liver plays an key role in the regulation of whole-body metabolism, and a fatty liver has been linked to metabolic abnormalities, including insulin resistance, cardiometabolic diseases, and muscle loss. Muscle loss may have serious consequences in individuals as it results in poor physical performance and increased incidence of falls. Furthermore, skeletal muscle acts as a glucose reservoir; thus, individuals who lose muscle mass often enter a vicious cycle that leads to a decreased glucose control, to more muscle loss, and eventually to hospitalization, decreased quality of life, and death. It is therefore important to investigate the role of the fatty liver in the development of muscle loss. The liver exerts many of its effects by 'inter-organ cross-talk'; the liver produces proteins and secretes these into the systemic circulation to affect metabolism elsewhere. In a previous study, I showed for the first time that hepatic steatosis altered the protein secretory profile, and that this altered profile leads to insulin resistance in skeletal muscle. Hence, it was the aim of the current project to determine whether the fatty liver also drives muscle atrophy via inter-organ cross-talk. To investigate our research goal, we fed mice a low or a high fat diet to induce a fatty liver, after which the livers were excised and cut into thin slices. Secretion products from the lean and fatty liver slices were collected and placed on muscle cells to measure muscle protein synthesis and breakdown. Interestingly, protein breakdown was increased in muscle cells incubated with secretion products from the fatty liver slices, while there was no effect on protein synthesis. The results of this study support the hypothesis that secretion products from the fatty liver contribute to the development of muscle atrophy in individuals with NAFLD.
Mice were placed on a low (4.5% fat) or a high-fat diet (HFD; 45% fat) for 12 weeks to induce fatty liver, after which the livers were sliced and cultured to collect secretion products (conditioned medium; CM). To investigate the effect of the secretome of a fatty liver on skeletal muscle metabolism, secretion products from a lean and fatty liver were placed on muscle cells for 24 h. Glucose uptake, protein synthesis, protein breakdown, and gene expression were subsequently measured. Glucose uptake in muscle cells was not different between chow and HFD CM in the basal state. However, insulin increased glucose uptake by 46% in muscle cells exposed to chow CM and by 18% in muscle cells exposed to HFD CM, demonstrating impaired insulin sensitivity in the muscle cells incubated with HFD CM . Protein synthesis was not different muscle cells incubated with chow and HFD CM, but protein breakdown was increased by 27% in HFD CM compared with chow CM. RNA profiling showed that 197 genes were differentially expressed, of which 46 (23.4%) were upregulated and 151 (76.6%) were downregulated by HFD CM compared with chow CM. Pathway analysis revealed that pathways related to skeletal muscle metabolism, growth, and remodeling were affected. This study provided evidence that secretion products from a fatty liver increase muscle protein breakdown rates and affects pathways involved in muscle function and morphology. The study supports our hypothesis that a fatty liver contributes to the development of muscle atrophy in individuals with NAFLD.
Science and teaching: Results that have been obtained during the funding period of the Marie Curie, have been published in high impact specialized peer-reviewed international journals and presented at national and international scientific symposium/ conferences. I have incorporated the results of my studies in my teaching program. Clinicians: In addition to a broad scientific outreach, I communicate my finding to specialists and other care providers who work with NAFLD patients in hospitals. Through my collaborator, Prof. Olde Damink, I have be able to present my work to a larger network of gastroenterologists and hepatologists at MUMC+ and in the region. I have also presented my data at the MUMC+ science days, thereby targeting researchers, clinicians, nurses and supporting staff. Patients: I am in good contact with Mrs. J. Willemse, who is the chair of the Dutch liver patient association, and whom I have met during a NAFLD conference in 2018. We have planned a meeting in December 2021 to discuss how to bring the results of my latest study across to the members of the association. General public: I ensure that the outcomes of my studies will reach the general public. I collaborated with the Press and Science communications department of Maastricht University and have issued a “press release” to have results disseminated in magazines, newspapers. This information reaches affected individuals, health departments, researchers, policy makers, and health advocacy groups.
Science and teaching: Results that have been obtained during the funding period of the Marie Curie, have been published in high impact specialized peer-reviewed international journals and presented at national and international scientific symposium/ conferences. I have incorporated the results of my studies in my teaching program. Clinicians: In addition to a broad scientific outreach, I communicate my finding to specialists and other care providers who work with NAFLD patients in hospitals. Through my collaborator, Prof. Olde Damink, I have be able to present my work to a larger network of gastroenterologists and hepatologists at MUMC+ and in the region. I have also presented my data at the MUMC+ science days, thereby targeting researchers, clinicians, nurses and supporting staff. Patients: I am in good contact with Mrs. J. Willemse, who is the chair of the Dutch liver patient association, and whom I have met during a NAFLD conference in 2018. We have planned a meeting in December 2021 to discuss how to bring the results of my latest study across to the members of the association. General public: I ensure that the outcomes of my studies will reach the general public. I collaborated with the Press and Science communications department of Maastricht University and have issued a “press release” to have results disseminated in magazines, newspapers. This information reaches affected individuals, health departments, researchers, policy makers, and health advocacy groups.
Too often hepatic steatosis is considered a benign stage of NAFLD. Hence, my project holds great potential for creating scientific as well as societal impact. The key stakeholders of my work include:
Clinicians:
• My study will show the importance of preventing or reducing liver steatosis as a therapeutic to improve muscle health.
• Greater awareness regarding the role of the liver in the development of muscle dysfunction may lead to the timely implementation of intervention programs to assist in the preservation of muscle health; this will reduce the burden on clinical practice.
Patients:
• My research will raise awareness in patients with NAFLD, and encourage them to follow exercise and nutrition guidelines in order to prevent or slow down muscle function decline.
• My results will be applicable to patients with full-blown NAFLD, as well as other individuals characterized by hepatic steatosis, including elderly, patients with alcoholic fatty liver disease, individuals with obesity and persons with T2D.
Industry:
• My research will identify novel (protein) targets, which will pave the way for future strategies aimed at drug development.
• The results of my study may lead to the development of (dietary) supplements or protein-rich products, designed to be used to preserve muscle mass and muscle health.
Scientific community
• Identification of novel liver-secreted signature proteins that regulate muscle function will spike further in-depth research regarding the role and mechanism-of-action of these proteins.
• Outcomes may lead to more research regarding the development of effective lifestyle intervention programs targeted at decreasing liver fat or improving muscle health.
• The findings of my research are of interest to other scientific fields in which muscle dysfunction is investigated, e.g. COPD and cancer research.
Clinicians:
• My study will show the importance of preventing or reducing liver steatosis as a therapeutic to improve muscle health.
• Greater awareness regarding the role of the liver in the development of muscle dysfunction may lead to the timely implementation of intervention programs to assist in the preservation of muscle health; this will reduce the burden on clinical practice.
Patients:
• My research will raise awareness in patients with NAFLD, and encourage them to follow exercise and nutrition guidelines in order to prevent or slow down muscle function decline.
• My results will be applicable to patients with full-blown NAFLD, as well as other individuals characterized by hepatic steatosis, including elderly, patients with alcoholic fatty liver disease, individuals with obesity and persons with T2D.
Industry:
• My research will identify novel (protein) targets, which will pave the way for future strategies aimed at drug development.
• The results of my study may lead to the development of (dietary) supplements or protein-rich products, designed to be used to preserve muscle mass and muscle health.
Scientific community
• Identification of novel liver-secreted signature proteins that regulate muscle function will spike further in-depth research regarding the role and mechanism-of-action of these proteins.
• Outcomes may lead to more research regarding the development of effective lifestyle intervention programs targeted at decreasing liver fat or improving muscle health.
• The findings of my research are of interest to other scientific fields in which muscle dysfunction is investigated, e.g. COPD and cancer research.