Fitness tools that monitor your daily use of energy, from counting steps to tracking sleep, have exploded in popularity. Researchers are developing better noninvasive, high-resolution methods to estimate how well the fundamental source of that energy — your mitochondria — are working, and they have recently had some important successes. Mitochondria are the tiny energy factories of our cells, and when they are not functioning properly, multiple downstream effects can result, including genetic mitochondrial diseases.
Mitochondrial dysfunction also occurs in common metabolic conditions like type 2 diabetes and obesity. The cellular energy crisis that occurs in genetic mitochondrial diseases primarily causes problems in a patient’s brain, heart, and muscle — organs that have high energy demands. However, since mitochondria are structures within almost every single cell of the human body, multiple organ systems may be involved, and symptoms can range from mild to severe, fluctuating over the course of mitochondrial diseases.
Scientists can measure a patient’s mitochondrial function using a technique that requires a muscle biopsy, but Shana McCormack, MD, MTR, an attending physician in the division of Endocrinology and Diabetes at CHOP, wanted to find a noninvasive method that could be used longitudinally to study the impact of metabolic diseases, especially for children. She helped colleagues at the University of Pennsylvania’s Center for Magnetic Resonance and Optical Imaging to refine novel magnetic resonance imaging (MRI) studies of muscle mitochondrial function.
More precisely, this new approach, called creatine chemical exchange saturation transfer (CrCEST) MRI, can detect changes in muscle creatine content before and after exercise that allow estimation of mitochondrial oxidative phosphorylation (OXPHOS) capacity, an important indicator of energy production. The main advantages of CrCEST are that it is noninvasive, avoiding the need for a muscle biopsy, and that it provides excellent anatomic resolution, allowing researchers to assess mitochondrial function in different muscle groups simultaneously.
“The effects of mitochondrial dysfunction can be very different depending on the muscle or tissue, so having the ability to look at different areas simultaneously, as opposed to making many muscle biopsies, has a real advantage,” Dr. McCormack said.
In a paper published in the November issue of JCI Insight, the research team demonstrated that CrCEST is a viable technique to measure OXPHOS capacity after exercise in individuals with genetic mitochondrial diseases. This new tool will help researchers to gain insights into mitochondrial bioenergetics and may provide an objective biomarker for clinical treatment trials so that they can determine if an intervention is helping a patient’s mitochondria to function better.
Another potential future direction of this new imaging modality is to study the question: What is the role of mitochondrial dysfunction in muscle in precipitating diabetes? Dr. McCormack investigates potential common pathways of mitochondrial dysfunction in patients with diabetes and patients with genetic mitochondrial disorders. Patients with mitochondrial diseases are at increased risk of diabetes, even if they’re not obese.
“There are known problems with pancreatic beta cells that produce insulin in those individuals, but what has has been studied less is insulin resistance in the muscle that we think may correspond to the degree of muscle mitochondrial impairment,” Dr. McCormack said. “In order for me to study diabetes risk in these individuals, it’s helpful to have a measure of muscle mitochondrial dysfunction. Then the next question is: Does muscle uptake of glucose depend on the degree of OXPHOS capacity? And if it does, this might be an area to intervene to prevent the development of diabetes, in individuals with mitochondrial diseases as well as individuals with ‘common’ type 2 diabetes.”
For example, exercise often is recommended as a part of mitochondrial disease therapy. Using the new MRI-based technique, researchers can do better studies on how exercise changes mitochondrial OXPHOS capacity, which patients are most likely to benefit from exercise, and other ways to augment those effects.
“I see a lot of really neat future directions where we can take this new measurement tool,” said Dr. McCormack, who also is an assistant professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. Read more about her research on disorders of energy balance in our blog.