RING finger protein 5 may guide treatment for muscle disease in ol... (team developed three mouse models: one k...)

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

Date:4/4/2008

team developed three mouse models: one knockout model in which the RNF5 gene was missing, and two in which cells could be triggered to overproduce RNF5, with expression either limited to skeletal muscle, -or within muscle and a variety of other organs.

A comparison of normal and knockout mice exposed to muscle-damaging toxin showed slower healing in the knockouts compared with the normal mice, demonstrating the importance of RNF5 in muscle repair.

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
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Contact: Andrea Moser
amoser@burnham.org
858-646-3146
Burnham Institute
Source:Eurekalert

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

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