Chaperone Proteins In Muscle Differentiation And Disease

see Vitadello et al. 2014a


This program investigates the role of molecular chaperones in striated muscle with special attention to their contribution to muscle atrophy development.
In fact, we demonstrated that the glucose-regulated protein Grp94, an endoplasmic reticulum chaperone, is involved in an interaction with nNOS in adult skeletal myofibers. Preservation of such an interaction, by increasing Grp94 expression either after genetical manipulation or pharmacological treatment with curcumin, maintains the physiological localization of the active nNOS enzyme at sarcolemma and attenuates the development of muscle atrophy secondary to muscle unloading (Vitadello et al. 2014a and b). Further investigations proved that the unloading-induced redistribution of active nNOS molecules from sarcolemma to sarcoplasm represents an atrophy master regulator, since it occurred already after a 6h unloading bout and was required for FoxO3 activation (Lechado i Terradas et al. 2018). The involvement of Grp94 and the efficacy of the curcumin treatment to antagonize muscle atrophy of the elderly (sarcopenia) are presently under study.
Our investigations on unloading muscle atrophy were then extended to melusin, a muscle-specific chaperone that participates in integrin signaling and is involved in the physiological regulation of cardiac muscle mass. Our study showed that unloading reduced early and severely melusin protein levels. Replacement with exogenous melusin attenuated the development of muscle atrophy, however, without restoring the physiological nNOS localization and inhibiting FoxO3. Indeed, only combined attempts to counteract the unloading-induced decrease of both melusin and Grp94 protein levels/active nNOS sarcolemmal localization succeeded in abolishing myofiber atrophy development. Last, but not least, these results prove that muscle atrophy development results from the independent requirement of more than a master regulator. The involvement of these chaperones in muscle atrophy secondary to denervation is presently investigated.

5 recent publications

  • Vitadello M, Sorge M, Percivalle E, Germinario E, Danieli-Betto D, Tarone G. Brancaccio M, Gorza L. (2020) Loss of melusin is a novel, neuronal NO synthase/FoxO3-independent master switch of unloading-induced muscle atrophy. J Muscle Cachexia Sarcopenia Muscle 11, 802-819 doi: 10.1002/jcsm.12546
  • Lechado i Terradas A, Vitadello M, Traini L, Namuduri AV, Gastaldello S, Gorza L. (2018) Sarcolemmal loss of active nNOS (Nos1) is an oxidative stress-dependent, early event driving disuse atrophy. J Pathol. 2018;246:433-46.
  • Gorza, L; Vitadello, M. 2018. Grp94 (HSP90B1) in Encyclopedia of Signaling Molecules, 2nd edition, S.Choi Ed. Springer International Publishing, New York,
  • Vitadello M, Gherardini J, Gorza L (2014a). The Stress Protein/Chaperone Grp94 Counteracts Muscle Disuse Atrophy by Stabilizing Subsarcolemmal nNOS. Antioxid Redox Signal 20:2479-2496.
  • Vitadello M, Germinario E, Ravara B, Dalla Libera L, Danieli Betto D, Gorza L. (2014b). Curcumin counteracts loss of force and atrophy of unloaded hindlimb rat soleus by hampering neuronal nitric oxide synthase untethering from sarcolemma. J Physiol 592:2637–2652


  • Institutional (ex 60%) and departmental (FINA) grants
  • PRAT 2015 CURAS: CURcumin Against Sarcopenia. Intervention against sarcopenia for healthy ageing: preclinical treatment using curcumin formulations with improved bioavailability.
  • BIRD2020 Role of melusin and Grp94/gp96 molecular chaperones in the denervated muscle (grant for one-year fellowship)