Breakthrough in fight against muscle wasting diseases
It is estimated that half of all cancer patients suffer from a muscle wasting syndrome called cachexia. Cancer cachexia impairs quality of life and response to therapy, which increases morbidity and mortality of cancer patients. Currently, there is no approved treatment for muscle wasting but a new study from the Research Institute of the McGill University Health Centre (RI-MUHC) and University of Alberta could be a game changer for patients, improving both quality of life and longevity. The research team discovered a new gene involved in muscle wasting that could be a good target for drug development.
The findings, which were published in September’s print edition of the FASEB Journal (Federation of American Societies for Experimental Biology), could have huge clinical implications, as muscle wasting is also associated with other serious illnesses such as HIV/AIDS, heart failure, rheumatoid arthritis and chronic obstructive pulmonary disease and is also a prominent feature of aging.
“We discovered that the gene USP19 appears to be involved in human muscle wasting and that in mice, once inhibited, it could protect against muscle wasting, ’’says lead author Dr. Simon Wing, MUHC endocrinologist and professor of Medicine at McGill University. “Muscle wasting is a huge unmet clinical need. Recent studies show that muscle wasting is much more common in cancer than we think.”
In this study, researchers worked with mice models that were lacking the gene USP19 (USP19 KO) and decided to look at two common causes of muscle wasting. They observed whether such mice were resistant to muscle wasting induced by a high level of cortisol – a stress hormone released in your body any time you have a stressful situation such as an illness or a surgery. They also looked at the loss of nerve supply because muscle atrophy can occur following a stroke when people are weak and bedbound. In addition, they looked at USP19 levels in human muscle samples from the most common cancers that cause muscle wasting: lung and gastrointestinal (pancreas, stomach, and colon).
“We found that USP19 KO mice were wasting muscle mass more slowly; in other words, inhibiting USP19 was protecting against both causes of muscle wasting,’’ explains Dr. Wing who is also the director of the Experimental Therapeutics and Metabolism Program at the RI-MUHC. “Our results show there was a very good correlation between the expression of this gene in the human muscle samples and other biomarkers that reflect muscle wasting.’’
According to recent studies, the prevalence of cachexia is high, ranging from 5 to 15 per cent in chronic heart failure and COPD, and from 60 to 80 per cent in advanced cancer. In all of these chronic conditions, muscle wasting predicts earlier death.
“Cancer patients often present with muscle wasting even prior to their initial cancer diagnosis,’’ says Dr. Antonio Vigano, director of the cancer rehabilitation program and cachexia clinic at the MUHC. “In cancer, cachexia also increases your risk of developing toxicity from chemotherapy and other oncological treatments, such as surgery and radiotherapy. At the McGill Nutrition and Performance Laboratory we specialize in cachexia and sarcopenia. By treating these two pathologic conditions through inhibiting the USP19 gene, at an early, rather than late, stage of the cancer trajectory, not only can we potentially improve the quality of life of patients, but also allow them to better tolerate their oncological treatments, to stay at home for a longer period of time, and to prolong their lives.’’
This study was supported by the Canadian Institutes of Health Research (CIHR) and the Terry Fox Research Institute (TFRI).
The article Inactivation of the ubiquitin-specific protease 19 deubiquitinating enzyme protects against muscle wasting is available online on the FASEB Journal website. The article was co-authored by Nathalie Bédard, Samer Jammoul, Tamara Moore , Marie Plourde, Erin Coyne, and Simon S. Wing, Polypeptide Laboratory and Crabtree Nutrition Laboratories, Department of Medicine, McGill University Health Centre; Stéphanie Chevalier, Crabtree Nutrition Laboratories, Department of Medicine, McGill University Health Centre; Linda Wykes, School of Dietetics and Human Nutrition, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada; Patricia L. Hallauer, Kenneth E. M. Hastings, Molecular Genetics Laboratory, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; Cynthia Stretch and Vickie Baracos, Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
About The Research Institute of the McGill University Health Centre
The Research Institute of the McGill University Health Centre (RI-MUHC) is a world-renowned biomedical and healthcare research centre. The Institute, which is affiliated with the Faculty of Medicine of McGill University, is the research arm of the McGill University Health Centre (MUHC) - an academic health centre located in Montreal, Canada, that has a mandate to focus on complex care within its community. The RI-MUHC supports over 500 researchers, and over 1,200 students, devoted to a broad spectrum of fundamental, clinical and health outcomes research at the Glen and the Montreal General Hospital sites of the MUHC. Our research facilities offer a dynamic multidisciplinary environment that fosters collaboration and leverages discovery aimed at improving the health of individual patients across their lifespan. Over 1,600 clinical research projects and trials are conducted within the organization annually. The RI-MUHC is supported in part by the Fonds de recherche du Québec - Santé (FRQS). www.rimuhc.ca
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Julie Robert
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McGill University Health Centre
julie [dot] robert [at] muhc [dot] mcgill [dot] ca
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