Senior research scientist
c/o Complesso Biologico Interdipartimentale
Viale Giuseppe Colombo 3
Endoplasmic reticulum stress-response and proteins
Our group investigates the endoplasmic reticulum stress-response in skeletal and cardiac muscle cells. In particular we are interested in unraveling the biological role of the glucose-regulated protein Grp94, a chaperone and a calcium-binding protein of the endoplasmic reticulum. Our investigations are performed in vitro, on myogenic cell lines, and in vivo, after genetic manipulation, in experimental models recapitulating several human diseases and in specimens obtained from affected patients.Grp94 is constitutively expressed in adult cardiac myocytes and in developing skeletal and cardiac muscle cells. In the adult, Grp94 gene is silenced in skeletal muscle cells(Vitadello et al. 1998). We hypothesized that such a tissue-restricted lack of responsiveness of the Grp94 gene was related to a specific functional role played by the protein during muscle differentiation. Our investigations with C2C12 cells demonstrated that Tyr-phosphorylation of Grp94 occurs soon after induction of differentiation and is required to redistribute the protein from the endoplasmic reticulum to the Golgi apparatus and cell surface (Frasson et al. 2009). Reduction of C2C12 Grp94 levels by mean of antisense cDNA is followed by loss of myotube formation. In contrast, overexpression of Grp94 enhances fusion ability of differentiating myoblasts (Gorza and Vitadello, 2000). In addition, increased expression of Grp94 plays a cytoprotective role in both skeletal and cardiac muscle cells against damage due to calcium overload, ischemia and oxidative stress (Vitadello et al. 2001 and 2003, Pizzo et al. 2009). Cytoprotection is due to the participation of the protein to the maintenance of calcium homeostasis, in that high cellular Grp94 levels decrease the amount of releasable calcium from the stores (Pizzo et al. 2009). Current investigations concern i) the contribution of Grp94 to the attenuation of skeletal muscle atrophy and ii) the development of strategies aimed to increase cellular Grp94 expression.
Vitadello M, Germinario E, Ravara B, Libera LD, Danieli-Betto D, Gorza L.Curcumin counteracts loss of force and atrophy of hindlimb unloaded rat soleus by hampering neuronal nitric oxide synthase untethering from sarcolemma. J Physiol. 2014 Jun 15;592(Pt 12):2637-52. doi: 10.1113/jphysiol.2013.268672. Epub 2014 Apr 7.
Vitadello M, Gherardini J, Gorza L. The stress protein/chaperone Grp94 counteracts muscle disuse atrophy by stabilizing subsarcolemmal neuronal nitric oxide synthase, Antioxid Redox Signal. 2014 Jun 1;20(16):2479-96. doi: 10.1089/ars.2012.4794. Epub 2013 Nov 26.
Vitadello M, Doria A, Tarricone E, Ghirardello A, Gorza L. Myofiber stress-response in myositis: parallel investigations on patients and experimental animal models of muscle regeneration and systemic inflammation. Arthritis Res Ther, 12: R52, 2010.
Pizzo P, Scapin S, Vitadello M, Florean C, Gorza L. Grp94 acts as a mediator of curcumin-induced anti-oxidant defence in myogenic cells. J Cell Mol Med. 14: 970-981, 2010.
Dalla Libera L, Ravara B, Gobbo V, Tarricone E, Vitadello M, Biolo G, Vescovo G, Gorza L. A transient anti-oxidant stress-response accompanies the onset of disuse atrophy in human skeletal muscle, J Appl Physiol 107: 549-557, 2009.