Advanced search
Start date
Betweenand

Mitochondria and endo/sarcoplasmic reticulum communication in skeletal muscle: role of mitofusins 1 and 2

Grant number: 22/09233-7
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): December 01, 2022
Effective date (End): November 30, 2023
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal Investigator:Julio Cesar Batista Ferreira
Grantee:Débora da Luz Scheffer
Supervisor: Ling Qi
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: University of Michigan, United States  
Associated to the scholarship:19/22204-3 - Mitochondrial dynamics in skeletal muscle: role of mitofusin 1 in health (exercise) and disease (Neurogenic Myopathy), BP.PD

Abstract

Impaired mitochondrial bioenergetics and defective endo/sarcoplasmic reticulum (ER) function have been individually reported in skeletal muscle under degenerative conditions in both humans and rodents. However, the dynamic interplay between these two key organelles under physiological conditions as well as its contribution to skeletal muscle degeneration remain elusive. Our preliminary findings demonstrate that combined skeletal muscle deletion of mitofusins 1 and 2 (mfn1/2 KO), critical proteins involved in mitochondria-ER tethering, is sufficient to induce a severe reduction in skeletal muscle mass and contractility properties (~50% decrease) when compared with wildtype littermates. It is important to highlight that these transgenic mice do not display dysfunctional skeletal muscle mitochondrial bioenergetics. Of interest, neurogenic myopathy changes the levels of proteins involved in both ER and mitochondrial calcium handling in skeletal muscle. Moreover, lack of skeletal muscle Mfn1/2 induces ER stress in both control (sham) and neurogenic myopathy. Here we propose to characterize the interplay between mitochondria and ER in skeletal muscle from wildtype mice under physiological and pathological (neurogenic myopathy) conditions. We also aim to understand the contribution of mitofusins 1 and 2 to mitochondria-ER interaction using mfn1/2 double KO mice. For that, we propose to access skeletal muscle mitochondria-ER tethering using 3D transmission electron microscopy (TEM), focused ion beam scanning electron microscopy (FIB-SEM), and proximity ligation assay (PLA). Moreover, we plan to measure mfn1 and mfn2 oligomerization and markers of ER stress including endoplasmic-reticulum-associated protein degradation (ERAD) and unfolded protein response (UPR). All these measurements will be performed in wildtype and double mitofusins 1 and 2 knockout mice under physiological and neurogenic myopathy conditions. Finally, we plan to evaluate mitochondrial, ER and cytosolic calcium handling and contractility properties in primary myoblasts isolated from WT and mitofusins 1 and 2 knockout mice. (AU)

News published in Agência FAPESP Newsletter about the scholarship:
Articles published in other media outlets (0 total):
More itemsLess items
VEICULO: TITULO (DATA)
VEICULO: TITULO (DATA)

Please report errors in scientific publications list using this form.