Zhang, Liping , Ph.D.
Satellite cell dysfunction and muscle atrophy in diabetes
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Insulin Action\Metabolism, Integrated Physiology\Insulin Resistance, Integrated Physiology\Muscle
Type of Grant: Basic Science
Project Start Date: January 1, 2011
Project End Date: December 31, 2013
Muscle wasting is a serious complication of diabetes and in patients, it not only reduces a patient's strength leading to loss of the benefits of exercise but the risk of death also increases. Unfortunately, the mechanisms causing diabetes-induced muscle wasting have not been fully identified. Consequently, it is difficult to design therapies to prevent muscle atrophy. Earlier, we found that diabetes stimulates the breakdown of protein in muscle while decreasing the synthesis of new muscle proteins. These defects contribute to the development of diabetes-induced muscle wasting. Recently, we uncovered another abnormality in mouse models of diabetes: satellite cell activities are defective. We investigatged satellite cells because they exert two benefits in muscle. First, when muscle is injured, satellite cells divide and proliferate to repair the injury. Therefore, defective satellite cell function could impair wound healing. Second, satellite cell activation and proliferation are necessary for the growth of muscle. Why are satellite cells abnormal? Diabetes generally increases the production of glucocorticoid hormones and we find this hormone impairs the function of satellite cells. We also found that myostatin, a hormone made in muscle, interferes with satellite cell function. We propose that glucocorticoids and myostatin contribute to the muscle wasting of diabetes. To test this hypothesis, we plan to study mice with diabetes being treated to prevent responses to glucocorticoids and/or myostatin. Our goal is to identify potential therapeutic strategies for preventing the muscle wasting of diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Muscle wasting is a serious complication of diabetes because it reduces a patient's strength, impairing the benefits of exercise and limits a patient's ability to repair muscle injuries, raising the risk of morbidity. I am investigating the function and significance of satellite cells and specifically, how type I or II diabetes contribute to the dysfunction of satellite cells. Overall, I am interested in why diabetic patients lose muscle mass and develop limited ability to heal injured muscles. My interest in satellite cells arises from earlier studies in which we found in models of diabetes in rodents stimulates the muscle protein breakdown and decreases the synthesis of new muscle proteins. These metabolic defects are not the only problem, however, because we recently determined that functional defects in satellite cells lead to additional abnormalities: reduced ability of satellite cells to proliferate and repair muscle wound/injury; and secondly, defects in satellite cell activation and proliferation will impair muscle growth. I plan to study the mechanisms for these defects, including different mediators that impair cell functions. For example, diabetes increases the production of glucocorticoid hormones and our preliminary results indicate that hormone impairs satellite cell function. Secondly, we have found that myostatin, a muscle hormone that regulates muscle cell growth, interferes with satellite cell function. Thus, we propose that in response to diabetes, glucocorticoids plus myostatin initiate muscle wasting. Our ultimate goal is to identify potential therapeutic strategies that will prevent the muscle wasting arising from impaired satellite cells and improve satellite cell function.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
People with diabetes tend to lose muscle mass which reduces their ability to exercise and enjoy life. In addition, diabetes can interfere with an individual's ability to repair an injury to muscle. These two defects are linked because we have found that diabetes interferes with the function of satellite cells, a type of 'stem' cell that is found in muscle. These cells are necessary for building new muscle and for repairing injuries to muscle. Experimentally, I have found that the function of satellite cells can improve to increase muscle mass and even correct the abnormal function of these cells so they act more effectively in repairing injured muscles.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Diabetes is a major problem for people around the world. Both of my parents have diabetes as do many of their friends. They have become less mobile, in part because of fatigue and potentially, loss of muscle mass. Fortunately, my parents have not had muscle injury but they have told me of friends that this is a dreaded consequence of diabetes because there is impaired healing of wounds.
The major goal of my research has been to try and understand how catabolic conditions, including diabetes cause muscle atrophy. Previously, we determined that diabetes accelerates muscle protein degradation by activating caspase-3 and the ubiquitin-proteasome system. These proteases contribute to muscle atrophy but there are other defects in muscle metabolism. Recently, we studied a method of inhibiting the function of myostatin, a hormone that suppresses muscle growth. When we blocked myostatin, the function of satellite cells improved along with the ability to build new muscle and repair muscle injury.
In addition, I am very grateful to the American Diabetes Association for the funds that will be used to develop my ideas and abilities. The opportunity for expanding my abilities and develop new ideas is a dream come true for me as a young investigator.
In what direction do you see the future of diabetes research going?
Diabetes is a world-wide health problem and the WHO projects that the number of individuals with diabetes will double in the next decade or so. Diabetes and its complications affect more than 50 million individuals in the US and lead to more than 300 billion dollars in health care costs each year. Clearly, this is a major health problem and will have to be combated by collaborative research efforts from individuals in a variety of scientific fields. I plan to use my background in cell biology but I will need the assistance of individuals from other disciplines such as clinical studies, biology, genomics, proteomics, bioinformatics, and statistics. With these concerted efforts, more hypothesis-testing projects and hypothesis-generating studies can result but the key will be for more MDs and PhDs to work together to find a cure for diabetes.
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