Effects of calorie restriction and exercise in the skeletal muscle protein aggregration

• Grant number: 19/22512-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): February 15, 2021
• Effective date (End): February 14, 2022
• Field of knowledge: Biological Sciences - Physiology - Physiology of Effort
• Principal Investigator: Eduardo Rochete Ropelle
• Grantee: Barbara Moreira Crisol
• Supervisor: Johan Auwerx
• Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
• Research place: École Polytechnique Fédérale de Lausanne (EPFL), Switzerland
• Associated to the scholarship: 18/04192-5 - Evaluation of the Parilation and the Mitonuclear Imbalance and the UPRmt in the Skeletal Musculature of Mice in Overtraining., BP.DR

Abstract

The aging process is characterized by a progressive loss of physiologic integrity, leading to impaired function, reducing the physical and mental capacity, increasing the risk of disease and finally increasing vulnerability to death. Changes in the body composition may influence the lifespan, once there is an increasing in the fat mass and a decrease in muscle mass during the aging process. The progressive loss of muscle mass and function is termed sarcopenia and is an age-related problem influenced by lifestyle and genetic factors. During aging, the loss and/or reduction activity of multiple cells may result in alterations in the mechanisms of proper folding, refolding or degradation of proteins, leading to protein aggregation, intra or extracellular. Protein aggregates are characteristics in several diseases, as Alzheimer's and Parkinson's disease in the nervous system, alcoholic steatohepatitis in the liver and even in the skeletal muscle as myopathy. Hitherto, there is no causative therapies available and the progression of the disease leads to severe disability and premature death. Preliminary data (not published) from the Laboratory of Integrative Systems Physiology (LISP) observed that aged mice presents amyloid aggregates in the skeletal muscle, especially when are exposed to high fat diet, suggesting that proteotoxic muscle diseases might be consequence from amyloidosis during aging and might be influenced by environmental factors. The mechanism of mitochondrial stress response (MSR) increases life span and the same mechanism, when activated prevents amyloid aggregation in Alzheimer's disease (AD) model. The MSR mechanism involves the activation of the unfolded protein response in the mitochondria (UPRmt) and the mitophagy. Meanwhile, the calorie restriction (CR) and physical exercise proved themselves important strategies increasing lifespan and improving health by activating AMP-activated protein kinase (AMPK) and Sirtuins (SIRTs) and increases NAD+ levels, both proteins that play a positive role in during extension of lifespan and health aging. Besides that, physical exercise is responsible to maintain muscle mass and it is primary treatment to sarcopenia. Since CR and exercise can increases NAD+ levels and activated SIRTs, which are involved in the activation of MSR, which seems to be an important mechanism to prevent amyloid aggregation during AD, we hypothesize that CR and exercise may improves mitochondrial dysfunction during aging or skeletal muscle disease and reduces amyloid aggregation, preserving skeletal muscle function. (AU)