Irisin and Therapeutics for Duchenne Muscular Dystrophy
Abstract
Duchene muscular dystrophy is an X-linked disease that is caused by a mutation in the dystrophin gene. About 1 in 5,000 boys are born with this disease, which causes progressive muscle weakness and muscle inflammation, as well as cardiac and diaphragm dysfunction. Even with current palliative measures, patients usually die in their 20s due to cardiac and breathing disorders. Exercise is known to improve function of skeletal muscles, heart, and diaphragm, but patients with DMD are very limited in their capacity to exercise. It is therefore of interest that we discovered irisin in 2012 as a polypeptide secreted by skeletal muscle and increased with endurance exercise in mice and humans. Tandem mass spectrometry of human plasma has demonstrated the structure of the irisin molecule in blood and shown definitively that it is increased with endurance exercise in human study groups. Previous studies have shown clear exercise-like effects of irisin on bone and adipose cells; more suggestive studies have observed effects on muscle tissues in mice. We therefore propose experiments to examine the effects of irisin in mdx mice, which carry a dystrophin mutation. These mice, on the B10 or D2 background, do not get as dysfunctional as DMD boys, but they do show reduced function in many parameters of skeletal muscle and heart. Irisin will be applied in these animals, initially using viral vectors, which will cause irisin to be secreted from the liver. Preliminary data is very promising, showing that this hormone improves running times and grip strength in three separate cohorts of mice. We will also determine, with the lab of Anthony Rosenzweig, whether these irisin treatments also improve cardiac function in the mdx mice. The critical molecular pathways providing these benefits will be explored using RNA, protein, and metabolite datasets obtained from the muscles of treated and untreated mice. Hypotheses thus developed will be tested by combining the irisin treatments with genetic mutations in key components of these pathways. We have already observed that the transcriptional component PGC1alpha is elevated by irisin treatment, so we will immediately proceed to test the hypothesis that this induction is a critical component of the benefits of irisin. Finally, we have formed a collaboration that supplies us with large amounts of highly purified irisin protein. We do not know whether it is better to have steady levels of irisin, as achieved with the viral vectors, or whether irisin performs better in mdx animals when allowed to oscillate, as might be expected for molecules linked to periodic bouts of exercise. We will begin to treat mice with recombinant irisin protein contained within osmotic pumps, which will deliver a fairly steady blood level, for 1 month. Functional parameters will again be measured. Alternatively, we will inject irisin directly into the mice three times a week, knowing that this will cause blood levels that will rise dramatically and diminish fairly quickly, since irisin has a fairly rapid clearance rate. Function of muscle and heart will be compared between these two treatment methods. It is expected that these studies will enable the development of either the “natural” irisin molecule or other versions of this molecule, which can be tested in human patients with DMD. This should be applicable to all DMD patients, regardless of his specific mutation. And since irisin will reach most or all tissues, it may improve multiple aspects of the disease. Since irisin is a natural hormone that rises and falls with exercise, we know of no data to suggest that this will have unacceptable side effects in patients with such a serious illness. These studies will likely highlight this pathway in the DMD field and motivate studies combining irisin with other therapies. The studies presented here will be completed within 2 years of funding of this proposal.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110611
Entities
People
- Bruce Spiegelman
Organizations
- Dana–Farber Cancer Institute
- United States Army