Failure of muscle homeostasis in oxidative stress response
Venue: Edificio Povo 2, via Sommarive nr. 9, Povo (Tn) - Room B102
At 2:00 p.m.
- Ester Zito - Laboratory of Signal transduction and Dulbecco Telethon Scientist Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
The Unfolded Protein Response (UPR) is an ancient multi-dimensional signaling pathway initiated by a mismatch between the unfolded Endoplasmic Reticulum (ER) protein load and the capacity of the ER to fold proteins that is known as ER stress. Usually the UPR helps relieve cells from ER stress so, it serves as an important pro-survival pathway. However, high levels of ER stress persist if a “maladaptive UPR” fails to re-establish ER homeostasis and consequently cells are committed to degeneration and programmed death. The findings of recent studies of lower eukaryotes suggest that ER hyper-oxidising conditions may lead to a change from an adaptive to a maladaptive UPR, but little is still known about the contribution that ER hyperoxidation makes to homeostatic failure and the related dysfunction of stressed mammalian cells. ER stress is one of the main processes triggered in skeletal muscle by altered environmental cues, and ER hyperoxidation has been associated with changes in calcium handling and muscle dysfunction. This straightforward connection between ER redox poise and calcium physiology makes muscle an ideal test organ for investigating the molecular steps involved in the change from an adaptive to a maladaptive UPR. In an attempt to clarify the molecular and physiological basis of ER redox-driven effects on muscle, we have established an innovative multi-faceted approach that combines genetic manipulations in mice with calcium measurements. The main objectives of this study are: 1) to characterise the molecular mechanisms connecting changes in ER redox poise with muscle physiology; and 2) to modulate the muscle redox milieu in vivo in order to test the impact of enhanced cell redox capacity on muscle performance and physiology.
