Effect of voluntary physical exercise on the establishment and progression of Amyotrophic Lateral Sclerosis (ALS) in SOD1G93A mutant mice

• Grant number: 25/05724-4
• Support Opportunities: Scholarships in Brazil - Master
• Start date: February 01, 2026
• End date: January 31, 2028
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Marucia Chacur
• Grantee: Nayara Veloso Rocha
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects approximately 0.01% of the world population (approximately 10 cases per 100,000 people). Most patients with familial or sporadic ALS present progressive degeneration of upper and lower motor neurons, leading to muscle atrophy, respiratory failure and death. In this sense, the development of preventive and therapeutic actions capable of mitigating the progression of ALS is of extreme importance. Scientific evidence suggests that physical exercise can mitigate the progression of neurodegenerative diseases such as Alzheimer's and Parkinson's, improving synaptic plasticity, reducing oxidative stress, promoting neurogenesis and decreasing the inflammatory response. However, in the case of ALS, the effects of physical exercise are quite controversial. Exercise at light and moderate intensities is protective, while exercise at high intensities is associated with more accelerated progression of the disease.Considering that exercise intensity is directly associated with mitochondrial bioenergetic mobilization, which is impaired in ALS, we believe that lower metabolic overloads resulting from light and moderate exercise increase mitochondrial efficiency in tissues directly affected by ALS and, consequently, are protective. However, proof-of-concept studies evaluating the effects of light/moderate exercise on mitochondrial bioenergetic metabolism in the motor cortex, spinal cord and skeletal muscle throughout the progression of ALS are lacking.Based on this information, we hypothesize that the improvement in ALS prognosis resulting from voluntary physical activity (light/moderate) is directly associated with the improvement of mitochondrial bioenergetic metabolism in tissues directly affected by the disease. To test this hypothesis, we will evaluate the potential of voluntary physical activity to improve mitochondrial bioenergetic metabolism in the motor cortex, spinal cord and skeletal muscle in moderate and advanced stages of ALS in SOD1-G93A transgenic mice. In addition, we will evaluate whether the improvement in mitochondrial energy metabolism resulting from physical exercise is associated with functional, morphological and biochemical aspects in tissues affected by ALS.For this study, we will use genetically modified male mice (SOD1-G93A), which develop ALS due to overexpression of the human SOD1-G93A enzyme. The animals will be randomized into four experimental groups: sedentary wild-type, exercised wild-type, sedentary SOD1-G93A, and exercised SOD1-G93A. At 30 days of age, the mice will be transferred and kept in individual cages with environmental enrichment, with or without free access to the running wheel. The impact of voluntary physical activity on disease progression will be evaluated throughout the pre-symptomatic (60 days of age), moderately symptomatic (110 days of age), and severely symptomatic (150 days of age) phases using behavioral and functional tests, such as rotarod, open field test, assessment of maximal motor capacity through the treadmill test, and assessment of muscle contractility ex vivo.In addition, we will perform biochemical analyses to assess oxygen consumption and hydrogen peroxide release from mitochondria isolated from ALS target tissues (motor cortex, spinal cord, and skeletal muscle). Finally, we will perform histological analyses to assess the morphology and inflammatory responses of the affected tissues. This study is extremely relevant, since understanding how physical activity interferes with mitochondrial bioenergetic metabolism in the tissues directly affected by ALS will contribute to the development of more effective non-pharmacological interventions in the treatment of ALS. It is worth mentioning that all the experimental procedures mentioned have already been standardized in the laboratory, ensuring the viability and feasibility of the project within the deadline stipulated for the master's scholar (AU)