RING finger protein 5 may guide treatment for muscle disease in older adults

Pathologic changes within muscles of the transgenic models with RNF5 overexpression were similar to those found in muscle biopsies from patients with sIBM. Overproduction of RNF5 caused a rapid and significant muscle degeneration, weight loss and muscle weakness. Followed by extensive muscle regeneration. Similar to what is often seen in patients with IBM, muscle specimens from RNF5 overexpressing animals revealed the presence of structures known as rimmed vacuoles and congophilic inclusions, hallmarks of this disease.

The researchers also found increased levels of markers characteristic of ER stress, a phenomenon that has been linked with a variety of human diseases, including sIBM. It is believed that ER stress is a response to misfolded-protein buildup; sensing the backlog, the ER recruits helpers through the Unfolded Protein Response (UPR)—chaperonins that increase the export of misfolded proteins to enable their breakdown and recycling. But, with prolonged stress, the UPR eventually fails to handle the overload, resulting in the accumulation of misfolded proteins in the cytoplasmic vacuoles, structures within the cell cytoplasm which are characteristic of sIBM patients.

Whether RNF5 is the primary cause for sIBM, or an important contributor in the development of this muscle disorder is yet to be determined. Dr. Ronai, lead author of the study, says the link established between ER stress, RNF5 and sIBM strengthen one theory stating that ER stress is causative for the disease and will now allow further study of the mechanisms underlying this disabling and all too common muscle disease.

“We now have a great mouse model that can be used to screen for drugs that might alleviate symptoms of sIBM,” says Dr. Ronai. But questions about what may interact with RNF5 in the cell to cause the symptoms of sIBM, he explains, still need to be addressed. “We know the substrates for this ubiquitin ligase in C. elegans, but not yet in human muscle.”

This research is supported by a grant from the National Cancer Institute of the National Institutes of Health.

About Burnham Institute for Medical Research

Burnham Institute for Medical Research uses an entrepreneurial, collaborative approach to medical research to reveal the fundamental molecular causes of disease and devise the innovative therapies of tomorrow. The Institute is organized into five research centers: a National Cancer Institute-designated Cancer Center; the Del E. Webb Center for Neurosciences, Aging and Stem Cell Research; an Infectious and Inflammatory Disease Research Center; a Diabetes and Obesity Research Center; and the Sanford Children’s Health Research Center. Thanks to the quality of its faculty members, Burnham ranks among the top 25 organizations worldwide (according to the Institute for Scientific Information) for its research impact and among the top four research institutes nationally for NIH grant funding. Burnham is a nonprofit, public benefit corporation headquartered in La Jolla, California, with campuses in Orlando, Florida and Santa Barbara, California. For more information, please visit www.burnham.org.