La titine est une protéine géante exprimée dans les muscles squelettiques et cardiaque. Un certain nombre de mutations pathogéniques ont été identifiées dans son dernier exon codant. La mutation la plus fréquente, FINmaj, conduit au remplacement de 4 acides aminés et est retrouvée chez de nombreux patients en Finlande. Cette mutation cause une dystrophiemusculaire tibiale (TMD) à l‟état hétérozygote et une dystrophie des ceintures de type 2J(LGMD2J) à l‟état homozygote.Pour obtenir une modèle d‟étude de la physiopathologie de ces maladies et évaluer des stratégiesthérapeutiques, nous avons introduit la mutation FINmaj dans le génome murin par une stratégiede Knock-In par recombinaison homologue. Ce modèle a été caractérisé et a permis de montrer qu‟il reproduit en grande partie les symptômes de la TMD et de la LGMD2J aux niveaux histologique et moléculaire. L‟étude de ce modèle murin a permis une meilleure compréhension de la physiopathologie de ces deux maladies et nous amené à étudier plus attentivement les interactions de la titine en C-ter avec ses partenaires afin de mieux comprendre l‟implication de la ligne M dans la vie du sarcomère. L‟ étude de la physiopathologie de la TMD et de la LGM2J a permis de montrer que la calpaïne 3 (une protéase à l‟origine d‟une autre dystrophie des ceintures), jouait un rôle majeur dans laTMD. Cette constatation nous a permis d‟envisager une approche thérapeutique pour cette dernière visant à diminuer les symptômes en régulant négativement la calpaïne 3. Une approche de thérapie génique a aussi été testée dans le but de traiter ces deux pathologies: le trans-épissage des derniers exons de la titine. En effet, étant donné la grande taille de l'ADNc de la titine (~100 kb), des stratégies classiques de transfert de gène n‟étaient pas envisageables. Pour s'affranchir de ce problème, nous avons testé une approche de trans-épissage de l‟ARN pour remplacer le ou les derniers exons du messager de la titine. Nous avons pu ainsi démontrer la faisabilité de la correction de la titine in vitro. / Titin is a giant protein expressed in both skeletal muscles and heart. Several pathogenic mutations were identified in its last coding exon. The most frequent mutation commonly referred to as FINmaj, results in the replacement of 4 amino acids and affects a subset of patients in Finland. The mutation causes a Tibial Muscular Dystrophy (TMD) when present on one allele and a Limb Girdle Muscular Dystrophy phenotype 2J (LGMD2J) when present on both alleles.To obtain a model for studying the physiopathology of these diseases and evaluating therapeutic strategies, we introduced the FINmaj mutation in the murine genome by a knock-in strategy by homologous recombination. This model was characterized and showed that it reproduces mainly the symptoms of both the human TMD and LGMD2J at histological and molecular levels.The study of this mouse model has allowed a better understanding of the pathophysiology of these two diseases and we have to study more carefully the interactions beyond titin C-ter with its partners to better understand the involvement of the M line in life of the sarcomere.The study of the pathophysiology of TMD and LGM2J showed that calpain 3 (a protease thatlind to an other limb-girdle muscular dystrophy), played a major role in TMD. This finding allowed us to consider a treatment approach for TMD to reduce symptoms by regulating negatively calpain 3. A gene therapy approach was also tested: the trans-splicing of the last exon of titin.Indeed, given the large size of the cDNA of titin (~ 100 kb), conventional strategies of genetransfer were not envisaged. To overcome this problem, we tested an approach to exchange the last exon or the last exons of the titin messenger. We were able to demonstrate the correction of titin in vitro.

No description available.

The giant protein titin is the third myofilament in the cardiac sarcomere. It is responsible for generating passive forces in stretched myocardium and maintaining sarcomere structure. The force generation properties of titin are determined by titin's elastic springlike elements, and this dissertation focuses on the determination of the physical properties of these springlike elements using atomic force microscopy. The primary project of this dissertation investigates the link between a single point mutation in one of titin's subdomains and arrhythmogenic cardiomyopathy.

Chapter 1 of this work focuses on alternative splicing of titin as a proof of concept therapy for treating diastolic dysfunction and restrictive filling in a genetic murine model (Ttn^(ΔIAjxn)). The Ttn^(ΔIAjxn) mouse has increased strain on the spring region of titin and acts as a mechanical analogue of the titin-based increase in passive myocardial stiffness found in patients with heart failure and preserved ejection fraction (HFpEF). HFpEF is a complex disease characterized by diastolic dysfunction, exercise intolerance, and concentric hypertrophic remodeling. Approximately half all of heart failure patients suffer from diastolic dysfunction, however, no effective therapy exists for treating this pervasive syndrome. Titin, the largest known protein and molecular spring in the heart, has emerged as a prime candidate for therapeutic targets aimed at restoring compliance to the sarcomere in order to improve diastolic function. Titin has two main cardiac isoforms that are regulated by alternative splicing; the smaller N2B isoform (~3.0 MDa) and the larger more compliant N2BA isoform (~3.3 MDa). Diastolic stiffness of the left ventricle is dependent upon the N2BA:N2B isoform ratio. In the first half of this work, we modified these two primary isoforms by inhibiting the known titin splicing factor Rbm20. We demonstrate that Rbm20 reduction restores diastolic function, improves exercise tolerance and attenuates afterload induced pathologic remodeling of the left ventricle in Ttn^(ΔIAjxn) mice.The work in chapter 2 is focused on studies using the previously published N2B knock out (KO) murine model. The N2B spring element found in cardiac titin's I-band region has been proposed as a sensor and signaling "hot spot" in the sarcomere. This study investigates the role of titin's cardiac specific N2B element as a mechano-sensor for stress and strain induced remodeling of the heart. The N2B KO mouse was subjected to a variety of stressors including transverse aortic constriction (TAC), aortocaval fistula (ACF), chronic swimming, voluntary running and isoproterenol stimulation. Our data revealed that the N2B element is essential in preload stimulated cardiac hypertrophy as well as remodeling due to beta-adrenergic stress. Cardiac hypertrophy is a common maladaptive feature of heart failure patients and the mechanical triggers that determine pathologic growth are not well understood. My work in the N2B KO mouse reveal titin's important role in cardiac remodeling.

In the first half of this work, titin's role in cardiac function was studied using intact cardiac myocytes. The development of a carbon fiber based cell-attachment system allowed diastolic and systolic function of the isolated intact myocyte to be investigated. Addition of actomyosin inhibitor to the intact myocyte revealed that the majority of the cell's diastolic stiffness is due to titin but that actomyosin interaction exists as well and contributes ~ 30% of total diastolic stiffness. The details of this study are provided in chapter 1. Heart failure with preserved ejection fraction (HFpEF) accounts for up to 50% of total heart failure cases and is characterized by increased diastolic stiffness. An effective treatment for HFpEF does not exist. Reducing titin stiffness as a therapeutic strategy for lowering left ventricular (LV) chamber stiffness in HFpEF is currently under consideration. To understand the functional consequence of reduced titin stiffness on global cardiac function a Rbm20 Δᴿᴿᴹ mouse model was created. The Rbm20 Δᴿᴿᴹ model has deficiency in titin splicing that results in expression of very large and compliant titin isoforms in the sarcomeres. Study of Rbm20 Δᴿᴿᴹ cells revealed that cellular diastolic stiffness was inversely related to the size of titin and was reduced in a graded manner in Rbm20 Δᴿᴿᴹ heterozygous (+/-) and homozygous (-/-) cells. Importantly, reduced titin-based stiffness manifested in vivo as reduced LV chamber stiffness, which could be observed by echocardiography and pressure volume (PV) analysis. The systolic function of Rbm20 Δᴿᴿᴹ was studied by measuring the Frank-Starling mechanism (FSM), first at the intact myocyte level. The FSM was reduced in Rbm20 Δᴿᴿᴹ +/- and -/- with the largest reduction in -/- cells. PV analysis demonstrated a reduced FSM at the LV chamber level, consistent with the result at the cellular level. Surprisingly, exercise testing showed an enhanced exercise performance in cardiac specific Rbm20 Δᴿᴿᴹ +/- mice (relative to wild-type mice). Thus, this work indicates that increasing titin compliance improves diastolic function but negatively impacts systolic function. Importantly, findings suggest that the beneficial effect of improving diastolic function is a dominant effect. This work is described in Chapter 2.

Universiẗat, Diss., 2003--Dortmund.

A literatura refere que os estímulos produzidos pelos diferentes tipos de contração no sistema músculo-esquelético geram adaptações específicas. A locomoção em aclive e declive vem sendo utilizada como modelo de treinamento concêntrico e excêntrico para estudos dessas adaptações em animais. Sendo assim este estudo teve o objetivo de avaliar características mecânicas e histológicas do músculo sóleo de ratos submetidos a treinamento em aclive ou declive. Foram avaliados 36 ratos Wistar machos (90 dias de idade no início do treinamento) divididos igualmente em três grupos: aclive (A), declive (D) e controle (C). Os treinamentos foram realizados em uma esteira adaptada com raias individuais e inclinação de + 16° (aclive) ou – 16° (declive). Os animais passaram por um período de adaptação de uma semana na esteira com a inclinação específica e, em seguida, foram avaliados quanto à velocidade máxima suportada. Os treinamentos aconteceram com velocidade (relativa à máxima avaliada) e tempo progressivos ao longo de oito semanas (29 sessões). Dois dias após o último treino os animais foram anestesiados com Tiopental Sódico (± 5 ml), os músculos sóleos direitos e esquerdos foram removidos e os animais decapitados. Os músculos sóleos da pata direita (n = 7C, 8A, 9D) foram submetidos a ensaios de tração em uma máquina EMIC DL2000, com célula de carga de 50 N a velocidade de 1,66 m·s-1. Durante o ensaio, as amostras foram borrifadas com solução salina a cada um minuto. Os músculos sóleos esquerdos foram retirados para contagem de sarcômeros (n = 4A, 4C e 5D) e análise na proteína titina por Western Blot (n = 4 por grupo). Foi verificada a normalidade e homogeneidade dos dados e a confiabilidade das medidas foi avaliada pelo coeficiente Alpha de Cronbach. Comportamentos individuais foram analisados pelo Coeficiente de Correlação Intraclasse (ICC); ANOVA one way e post hoc de Bonferroni e teste não paramétrico Kruskal-Walls foram aplicados para identificação das diferenças entre os grupos. Dos 36 animais, três morreram antes do final do experimento. Os coeficientes Alpha de Cronbach indicaram confiabilidade das medidas com valores próximos a um para todas as variáveis. Os dados mecânicos dos animais que treinaram em declive apresentaram menores valores de ICC, mesmo assim significativos. As comparações entre os grupos indicaram aumento significativo da rigidez da curva tensão X deformação para os animais treinados em aclive e declive, e maior deformação da curva para os animais controle. Foi encontrado aumento da média da tensão passiva dos músculos dos animais treinados (57 ± 5 e 56 ± 11 para A e D; 51,6 ± 7,7 para C), contudo essa diferença não foi estatisticamente significativa, possivelmente devido a grande variabilidade dos dados mecânicos. Em relação ao número de sarcômeros em série os animais que treinaram em declive apresentaram menores comprimentos de sarcômero (2,806 ± 0,059 μm) e maior número de sarcômeros em série (8170 ± 510) quando comparados aos grupos controle (3,06 ± 0,054 μm e 7510 ± 240) e aclive (2,990 ± 0,023 μm e 7390 ± 270). As demais variáveis analisadas não apresentaram diferenças entre os grupos. É possível concluir com este estudo que adaptações estruturais nem sempre acontecem em paralelo às adaptações funcionais, que o treinamento em declive parece produzir resultados com maiores variações e que os diferentes estímulos provocam diferentes adaptações no músculo sóleo de ratos. / The literature states that the stimulus produced by different types of contraction in skeletal muscle generates specific adaptations. Downhill and uphill locomotion have been used as a model of concentric and eccentric training in studies that verify the different adaptations in animals. Therefore this study intended to evaluate mechanical and histological properties of rats’ soleus muscle submitted to uphill or downhill running. We evaluated 36 male Wistar rats (90 days old at the start of training). They were divided equally into three groups: uphill (A), downhill (D) and control (C). Training was performed on a treadmill adapted to individual lanes and +16º (uphill) or -16º (downhill) incline. The animals went through a one week adjustment period on the treadmill with the specific inclines, and then there were evaluated the maximal speeds they reached. The training took place with progressive speed (relative to the maximum tested) and time over 8 weeks (29 sessions). Two days after the last training the animals were anesthetized with sodium thiopental (± 5 ml), the right and left soleus muscles were removed and the animals were decapitated. The right soleus muscles (n = 7C, 8A, 9D) were subjected to tensile tests on one machine EMIC DL2000, with a load cell of 50 N, speed of 1,66 m.s-1. During the test, the samples were sprayed with saline solution every one minute. The left soleus muscles were removed for counting of sarcomeres (n = 4A, 4C, 5D) and the titin Western blot analysis (n = 4 per group). Data normality and homogeneity were verified and reliability of the measures was assessed by Cronbach's Alpha coefficient. Individual behaviors were analyzed by Intraclass Correlation Coefficient (ICC); one-way ANOVA and post hoc Bonferroni test and nonparametric Kruskal-Wallis were applied to identify the differences between the groups. Three out of the 36 animals died before the end of the experiment. The Cronbach's Alpha coefficients indicated reliability of the measures with values close to one for all the analyzed variables. The mechanical data of downhill trained animals had significantly lower ICC, even though significant. Comparisons between groups showed increased rigidity of the muscles of trained animals and greater deformation of the muscles of control animals. It has been found greater passive tension mean for both training groups (57 ± 5 and 56 ± 11 for A and D; 51.6 ± 7.7 for C), but it was not statistically significant probably due to the high mechanical data variability. Regarding the number of sarcomeres in series the downhill trained animals showed smaller sarcomere lengths (2.806 ± 0.059 μm) and greater serial sarcomere number (8170 ± 510) when compared to control (3.06 ± 0.054 μm and 7510 ± 240) and uphill (2.990 ± 0.023 μm e 7390 ± 270) groups. The remaining variables did not differ between groups. It can be concluded from this study that structural adaptations do not happen in parallel with functional adaptations, downhill running appear to produce more variable results and that different stimuli generate different adaptations in rats’ soleus muscle.

A literatura refere que os estímulos produzidos pelos diferentes tipos de contração no sistema músculo-esquelético geram adaptações específicas. A locomoção em aclive e declive vem sendo utilizada como modelo de treinamento concêntrico e excêntrico para estudos dessas adaptações em animais. Sendo assim este estudo teve o objetivo de avaliar características mecânicas e histológicas do músculo sóleo de ratos submetidos a treinamento em aclive ou declive. Foram avaliados 36 ratos Wistar machos (90 dias de idade no início do treinamento) divididos igualmente em três grupos: aclive (A), declive (D) e controle (C). Os treinamentos foram realizados em uma esteira adaptada com raias individuais e inclinação de + 16° (aclive) ou – 16° (declive). Os animais passaram por um período de adaptação de uma semana na esteira com a inclinação específica e, em seguida, foram avaliados quanto à velocidade máxima suportada. Os treinamentos aconteceram com velocidade (relativa à máxima avaliada) e tempo progressivos ao longo de oito semanas (29 sessões). Dois dias após o último treino os animais foram anestesiados com Tiopental Sódico (± 5 ml), os músculos sóleos direitos e esquerdos foram removidos e os animais decapitados. Os músculos sóleos da pata direita (n = 7C, 8A, 9D) foram submetidos a ensaios de tração em uma máquina EMIC DL2000, com célula de carga de 50 N a velocidade de 1,66 m·s-1. Durante o ensaio, as amostras foram borrifadas com solução salina a cada um minuto. Os músculos sóleos esquerdos foram retirados para contagem de sarcômeros (n = 4A, 4C e 5D) e análise na proteína titina por Western Blot (n = 4 por grupo). Foi verificada a normalidade e homogeneidade dos dados e a confiabilidade das medidas foi avaliada pelo coeficiente Alpha de Cronbach. Comportamentos individuais foram analisados pelo Coeficiente de Correlação Intraclasse (ICC); ANOVA one way e post hoc de Bonferroni e teste não paramétrico Kruskal-Walls foram aplicados para identificação das diferenças entre os grupos. Dos 36 animais, três morreram antes do final do experimento. Os coeficientes Alpha de Cronbach indicaram confiabilidade das medidas com valores próximos a um para todas as variáveis. Os dados mecânicos dos animais que treinaram em declive apresentaram menores valores de ICC, mesmo assim significativos. As comparações entre os grupos indicaram aumento significativo da rigidez da curva tensão X deformação para os animais treinados em aclive e declive, e maior deformação da curva para os animais controle. Foi encontrado aumento da média da tensão passiva dos músculos dos animais treinados (57 ± 5 e 56 ± 11 para A e D; 51,6 ± 7,7 para C), contudo essa diferença não foi estatisticamente significativa, possivelmente devido a grande variabilidade dos dados mecânicos. Em relação ao número de sarcômeros em série os animais que treinaram em declive apresentaram menores comprimentos de sarcômero (2,806 ± 0,059 μm) e maior número de sarcômeros em série (8170 ± 510) quando comparados aos grupos controle (3,06 ± 0,054 μm e 7510 ± 240) e aclive (2,990 ± 0,023 μm e 7390 ± 270). As demais variáveis analisadas não apresentaram diferenças entre os grupos. É possível concluir com este estudo que adaptações estruturais nem sempre acontecem em paralelo às adaptações funcionais, que o treinamento em declive parece produzir resultados com maiores variações e que os diferentes estímulos provocam diferentes adaptações no músculo sóleo de ratos. / The literature states that the stimulus produced by different types of contraction in skeletal muscle generates specific adaptations. Downhill and uphill locomotion have been used as a model of concentric and eccentric training in studies that verify the different adaptations in animals. Therefore this study intended to evaluate mechanical and histological properties of rats’ soleus muscle submitted to uphill or downhill running. We evaluated 36 male Wistar rats (90 days old at the start of training). They were divided equally into three groups: uphill (A), downhill (D) and control (C). Training was performed on a treadmill adapted to individual lanes and +16º (uphill) or -16º (downhill) incline. The animals went through a one week adjustment period on the treadmill with the specific inclines, and then there were evaluated the maximal speeds they reached. The training took place with progressive speed (relative to the maximum tested) and time over 8 weeks (29 sessions). Two days after the last training the animals were anesthetized with sodium thiopental (± 5 ml), the right and left soleus muscles were removed and the animals were decapitated. The right soleus muscles (n = 7C, 8A, 9D) were subjected to tensile tests on one machine EMIC DL2000, with a load cell of 50 N, speed of 1,66 m.s-1. During the test, the samples were sprayed with saline solution every one minute. The left soleus muscles were removed for counting of sarcomeres (n = 4A, 4C, 5D) and the titin Western blot analysis (n = 4 per group). Data normality and homogeneity were verified and reliability of the measures was assessed by Cronbach's Alpha coefficient. Individual behaviors were analyzed by Intraclass Correlation Coefficient (ICC); one-way ANOVA and post hoc Bonferroni test and nonparametric Kruskal-Wallis were applied to identify the differences between the groups. Three out of the 36 animals died before the end of the experiment. The Cronbach's Alpha coefficients indicated reliability of the measures with values close to one for all the analyzed variables. The mechanical data of downhill trained animals had significantly lower ICC, even though significant. Comparisons between groups showed increased rigidity of the muscles of trained animals and greater deformation of the muscles of control animals. It has been found greater passive tension mean for both training groups (57 ± 5 and 56 ± 11 for A and D; 51.6 ± 7.7 for C), but it was not statistically significant probably due to the high mechanical data variability. Regarding the number of sarcomeres in series the downhill trained animals showed smaller sarcomere lengths (2.806 ± 0.059 μm) and greater serial sarcomere number (8170 ± 510) when compared to control (3.06 ± 0.054 μm and 7510 ± 240) and uphill (2.990 ± 0.023 μm e 7390 ± 270) groups. The remaining variables did not differ between groups. It can be concluded from this study that structural adaptations do not happen in parallel with functional adaptations, downhill running appear to produce more variable results and that different stimuli generate different adaptations in rats’ soleus muscle.

A literatura refere que os estímulos produzidos pelos diferentes tipos de contração no sistema músculo-esquelético geram adaptações específicas. A locomoção em aclive e declive vem sendo utilizada como modelo de treinamento concêntrico e excêntrico para estudos dessas adaptações em animais. Sendo assim este estudo teve o objetivo de avaliar características mecânicas e histológicas do músculo sóleo de ratos submetidos a treinamento em aclive ou declive. Foram avaliados 36 ratos Wistar machos (90 dias de idade no início do treinamento) divididos igualmente em três grupos: aclive (A), declive (D) e controle (C). Os treinamentos foram realizados em uma esteira adaptada com raias individuais e inclinação de + 16° (aclive) ou – 16° (declive). Os animais passaram por um período de adaptação de uma semana na esteira com a inclinação específica e, em seguida, foram avaliados quanto à velocidade máxima suportada. Os treinamentos aconteceram com velocidade (relativa à máxima avaliada) e tempo progressivos ao longo de oito semanas (29 sessões). Dois dias após o último treino os animais foram anestesiados com Tiopental Sódico (± 5 ml), os músculos sóleos direitos e esquerdos foram removidos e os animais decapitados. Os músculos sóleos da pata direita (n = 7C, 8A, 9D) foram submetidos a ensaios de tração em uma máquina EMIC DL2000, com célula de carga de 50 N a velocidade de 1,66 m·s-1. Durante o ensaio, as amostras foram borrifadas com solução salina a cada um minuto. Os músculos sóleos esquerdos foram retirados para contagem de sarcômeros (n = 4A, 4C e 5D) e análise na proteína titina por Western Blot (n = 4 por grupo). Foi verificada a normalidade e homogeneidade dos dados e a confiabilidade das medidas foi avaliada pelo coeficiente Alpha de Cronbach. Comportamentos individuais foram analisados pelo Coeficiente de Correlação Intraclasse (ICC); ANOVA one way e post hoc de Bonferroni e teste não paramétrico Kruskal-Walls foram aplicados para identificação das diferenças entre os grupos. Dos 36 animais, três morreram antes do final do experimento. Os coeficientes Alpha de Cronbach indicaram confiabilidade das medidas com valores próximos a um para todas as variáveis. Os dados mecânicos dos animais que treinaram em declive apresentaram menores valores de ICC, mesmo assim significativos. As comparações entre os grupos indicaram aumento significativo da rigidez da curva tensão X deformação para os animais treinados em aclive e declive, e maior deformação da curva para os animais controle. Foi encontrado aumento da média da tensão passiva dos músculos dos animais treinados (57 ± 5 e 56 ± 11 para A e D; 51,6 ± 7,7 para C), contudo essa diferença não foi estatisticamente significativa, possivelmente devido a grande variabilidade dos dados mecânicos. Em relação ao número de sarcômeros em série os animais que treinaram em declive apresentaram menores comprimentos de sarcômero (2,806 ± 0,059 μm) e maior número de sarcômeros em série (8170 ± 510) quando comparados aos grupos controle (3,06 ± 0,054 μm e 7510 ± 240) e aclive (2,990 ± 0,023 μm e 7390 ± 270). As demais variáveis analisadas não apresentaram diferenças entre os grupos. É possível concluir com este estudo que adaptações estruturais nem sempre acontecem em paralelo às adaptações funcionais, que o treinamento em declive parece produzir resultados com maiores variações e que os diferentes estímulos provocam diferentes adaptações no músculo sóleo de ratos. / The literature states that the stimulus produced by different types of contraction in skeletal muscle generates specific adaptations. Downhill and uphill locomotion have been used as a model of concentric and eccentric training in studies that verify the different adaptations in animals. Therefore this study intended to evaluate mechanical and histological properties of rats’ soleus muscle submitted to uphill or downhill running. We evaluated 36 male Wistar rats (90 days old at the start of training). They were divided equally into three groups: uphill (A), downhill (D) and control (C). Training was performed on a treadmill adapted to individual lanes and +16º (uphill) or -16º (downhill) incline. The animals went through a one week adjustment period on the treadmill with the specific inclines, and then there were evaluated the maximal speeds they reached. The training took place with progressive speed (relative to the maximum tested) and time over 8 weeks (29 sessions). Two days after the last training the animals were anesthetized with sodium thiopental (± 5 ml), the right and left soleus muscles were removed and the animals were decapitated. The right soleus muscles (n = 7C, 8A, 9D) were subjected to tensile tests on one machine EMIC DL2000, with a load cell of 50 N, speed of 1,66 m.s-1. During the test, the samples were sprayed with saline solution every one minute. The left soleus muscles were removed for counting of sarcomeres (n = 4A, 4C, 5D) and the titin Western blot analysis (n = 4 per group). Data normality and homogeneity were verified and reliability of the measures was assessed by Cronbach's Alpha coefficient. Individual behaviors were analyzed by Intraclass Correlation Coefficient (ICC); one-way ANOVA and post hoc Bonferroni test and nonparametric Kruskal-Wallis were applied to identify the differences between the groups. Three out of the 36 animals died before the end of the experiment. The Cronbach's Alpha coefficients indicated reliability of the measures with values close to one for all the analyzed variables. The mechanical data of downhill trained animals had significantly lower ICC, even though significant. Comparisons between groups showed increased rigidity of the muscles of trained animals and greater deformation of the muscles of control animals. It has been found greater passive tension mean for both training groups (57 ± 5 and 56 ± 11 for A and D; 51.6 ± 7.7 for C), but it was not statistically significant probably due to the high mechanical data variability. Regarding the number of sarcomeres in series the downhill trained animals showed smaller sarcomere lengths (2.806 ± 0.059 μm) and greater serial sarcomere number (8170 ± 510) when compared to control (3.06 ± 0.054 μm and 7510 ± 240) and uphill (2.990 ± 0.023 μm e 7390 ± 270) groups. The remaining variables did not differ between groups. It can be concluded from this study that structural adaptations do not happen in parallel with functional adaptations, downhill running appear to produce more variable results and that different stimuli generate different adaptations in rats’ soleus muscle.

No description available.