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Effects of eccentric exercise in skeletal muscle rehabilitation of mdx mice after long period of training: morphological, functional and molecular evaluations

Abstract

Duchene Muscular Dystrophy (DMD) is a recessive degenerative disease linked to the X chromosome. DMD is a result of changes in a gene with 79 exons, localized in the region Xp21 of X chromosome. DMD is caused by the absence of the protein dystrophin, which is essential for muscle integrity. A lack of dystrophin leads to muscle weakness and progressive degeneration, and eventually to death due to respiratory failure. Since DMD is a progressive and incapacitating disease, many strategies of physical therapy such as hydrotherapy and respiratory exercise have been used to provide greater comfort for patients affected by DMD. Eccentric exercise has been used such as rehabilitation methods in skeletal muscles after disuse procedures, and recently, they have been used in dystrophic muscles after rehabilitation with eccentric exercise. However, there is a limitation in the use of eccentric exercise: we still do not understand the molecular mechanisms involved in the reduction of contraction force in dystrophic muscles. Isokinetic analysis, computational dynamometry analysis, and manual analysis are methods frequently used to quantify reduction or increased of the force in dystrophic muscle, but they do not allow the understanding of the molecular mechanisms involved in the reduction of force in dystrophic muscles. In this project we propose to use single permeabilized fibers, which have been increasingly used in the fields of muscle physiology and biophysics, allowing for the precise evaluation of cross-bridge kinetics and structural components involved in muscle contraction in DMD. The method allows for a deep understand of the mechanisms of muscle contraction, and more specifically the kinetics of myosin cross-bridges and actin, the two major proteins involved in muscle contraction. We will analyze single permeabilized fibers dissected from DMD muscles, a technique that allows for an analysis of the decrease in strength with in DMD high accuracy. Furthermore, we will better understand the molecular processes involved in myofibril degeneration and to evaluate the effects of eccentric exercise applied during long period of rehabilitation on the contractile function of degenerating myofibers. Finally, the development of this project will enable the implementation of an accurate system for analysis of muscle cells in the physiotherapy research field, and in the Department of Pathology of the FMRP, creating new scientific collaborations with a renowned institution in Canada (McGill University). Methods: Male mice (four weeks old) will be divided into four groups: (i) mdx sedentary; (ii) mdx trained in treadmill running; (iii) wild type sedentary; (iv) wild type trained in treadmill running. Each group will be further divided into two subgroups according to the training duration: 3 days (acute phase) and 36 days (chronic phase). After the training sessions, animals will be euthanized, and fragments of soleus and diaphragm muscles will be removed for different analyses. Data collection will be performed using an inverted microscope and a single cell system (600A) from Aurora Scientific (Canada). Mechanical tests will be performed in both groups and the active and passive forces in different sarcomere lengths will be measured. The qualitative and quantitative analysis of the generic aspects and protein will be made with different biochemical and histological techniques. Expected results: muscles of mdx trained group will present improved cross-bridge kinetics at different sarcomere lengths and a significant increase in maximal isometric force. Furthermore the muscular tissue will show cellular regeneration through satellite cells proliferation. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
LEITE, FELIPE S.; MINOZZO, FABIO C.; KALGANOV, ALBERT; CORNACHIONE, ANABELLE S.; CHENG, YU-SHU; LEU, NICOLAE A.; HAN, XUEMEI; SARIPALLI, CHANDRA; YATES, III, JOHN R.; GRANZIER, HENK; et al. Reduced passive force in skeletal muscles lacking protein arginylation. AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, v. 310, n. 2, p. C127-C135, . (13/07104-6)
PEDRAZZANI, PAULO S.; ARAUJO, TATIANA O. P.; SIGOLI, EMILLY; DA SILVA, ISABELLA R.; DA ROZA, DAIANE LEITE; CHESCA, DEISE LUCIA; RASSIER, DILSON E.; CORNACHIONE, ANABELLE S.. Twenty-one days of low-intensity eccentric training improve morphological characteristics and function of soleus muscles of mdx mice. SCIENTIFIC REPORTS, v. 11, n. 1, . (17/03843-0, 13/07104-6, 18/07581-2, 17/00267-8, 16/21048-0, 13/25634-2)
HUSSAIN, SABAH N. A.; CORNACHIONE, ANABELLE S.; GUICHON, CELINE; AL KHUNAIZI, AUDAY; LEITE, FELIPE DE SOUZA; PETROF, BASIL J.; MOFARRAHI, MAHROO; MOROZ, NIKOLAY; DE VARENNES, BENOIT; GOLDBERG, PETER; et al. Prolonged controlled mechanical ventilation in humans triggers myofibrillar contractile dysfunction and myofilament protein loss in the diaphragm. THORAX, v. 71, n. 5, p. 436-445, . (13/07104-6)

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