Role of skeletal muscle mitofusin 1 in mitochondria-sarcoplasmic reticulum communication: impact of exercise training

• Grant number: 23/10317-3
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• Start date: October 31, 2023
• End date: February 28, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Julio Cesar Batista Ferreira
• Grantee: Jones Raul Laureano Meneses
• Supervisor: Ling Qi
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Virginia (UVa), United States
• Associated to the scholarship: 21/05746-7 - Role of mytofusin 1 in adaptations induced by physical exercise in skeletal muscle, BP.IC

Abstract

Mitochondria are organelles that continually undergo fusion and fission. These opposite processes work together to maintain the shape, size, number and function of mitochondria. Mitochondrial fusion proteins (mitofusins 1 and 2) also play key role in the mitochondria-endo/sarcoplasmic reticulum (ER) communication; therefore, affecting critical intracellular processes such as phospholipids synthesis/transferring and ionic balance. Our preliminary findings provide evidence that mice lacking skeletal muscle Mfn1 display reduced skeletal muscle contractility properties upon chronic running exercise regimen compared with their non-exercised littermates. Interestingly, these changes in muscle contractility properties in mice lacking skeletal muscle Mfn1 are independent of skeletal muscle mitochondrial function since both Mfn1 deficient and wildtype mice equally improved their skeletal muscle mitochondrial oxygen consumption after the exercise regimen. These findings clearly suggest that other Mfn1-dependent processes are critical to maintain skeletal muscle contractility properties upon exercise, which are dissociated from mitochondrial bioenergetics. Considering the key role of mitochondria-ER communication in calcium handling, we decided to characterize skeletal muscle mitochondria and ER morphologies as well as mitochondria-ER tethering in mice lacking skeletal muscle mfn1 and their wild type littermates, both exposed to sedentary or running exercise regimen. The exercised group will perform a 4-week protocol of running exercise, as previously described by our laboratory.For the morphological analyses, we will use 3D transmission electron microscopy (TEM) and focused ion beam scanning electron microscopy (FIB-SEM). Finally, we will measure in the skeletal muscle of these mice some markers of ER stress by western blot (BiP, Ire1±, PERK, ATF6, ATF4, eIF2±, p-eIF2±, CHOP, XBP1S, NRF2) to check whether disruption of mitochondria-ER communication through Mfn1 induces skeletal muscle ER stress. Note that all samples will be collected and prepared in Brazil prior to the interniship; therefore, guaranteeing the feasibility of the current proposal. (AU)