Abstract To investigate the turnover of type IV collagen in skeletal muscle in conditions where muscle function is impaired, type IV collagen and proteins regulating its degradation were studied during 1, 3 and 7 days of immobilization, 3- and 10-day glucocorticoid treatment and in neuromuscular diseases. In addition, fibrillar type I and III collagens were studied during immobilization and in neuromuscular diseases. The mRNA levels of type I, III and IV collagens were decreased during immobilization and during 10-day dexamethasone treatment. Gene expression and quantity of (pro)MMP-2 was increased during immobilization but decreased during dexamethasone treatment. The expression of TIMP-2 was decreased both during immobilization and dexamethasone treatment. Decreased gene expression and increased degradation caused decreased concentration of type IV collagen, suggesting net degradation of type IV collagen during immobilization. While the gene expression and degradation were decreased during dexamethasone treatment, the amount of type IV collagen was not changed. Dexamethasone thus seemed to slow down the turnover of type IV collagen. Decreased mRNA levels of collagens and prolyl 4-hydroxylase suggest decreased biosynthesis of collagens during immobilization. The mRNA levels of collagens I, III and IV were increased in polyneuropathy and polymyositis. The concentration and staining intensity of type IV collagen was increased in polyneuropathy, as was also the quantity and staining intensity of (pro)MMP-9. The results suggest accumulation of type IV collagen in the basement membranes of muscle cells and capillaries in polyneuropathy muscles. Lengthened position during immobilization partly prevented the atrophy and changes in collagen metabolism in plantarflexors. Endurance running was effective in preventing muscle atrophy during dexamethasone treatment, but exercise did however fail to prevent the changes observed in type IV collagen synthesis and degradation.

Abstract Genomic clones covering the entire mouse type XIII collagen gene (Col13a1) were isolated, and the complete exon-intron organization was characterized. The gene was found to be about 135 kb in size and to locate in the mouse chromosome 10. Comparison of gene structures and promoter regions between man and mouse indicated high conservation between the two species. In order to understand the biological function of type XIII collagen, a mouse line that expresses type XIII collagen with replacement of the cytosolic and transmembrane domains by a short, non-descript sequence was generated using homologous recombination. Expression of this aminoterminally altered type XIII collagen led to mild but progressive muscular atrophy in mice. The integrity of muscle cells was disturbed and the basement membrane showed areas of detachment from the sarcolemma as well as clearly altered structure at myotendinous junctions. These phenotypical changes were, nevertheless, local, since the majority of the muscle was intact. The results show the importance of the membrane anchorage of the type XIII collagen protein in adhesion and, consequently in the maintenance of muscle integrity. To study the significance of various regions of type XIII collagen, wild-type and mutant forms of the protein were produced recombinantly in insect cells. The transmembrane domain and the adjacent region of ectodomain were found to be crucial for the formation of type XIII collagen molecules with all of the three collagenous domains in trimeric conformation. A previously characterized conserved membrane-proximal region of the ectodomain was predicted to harbour a coiled-coil conformation. This was suggested to begin in the transmembrane domain of type XIII collagen and in several other collagenous transmembrane proteins. Type XIII collagen lacking this coiled-coil sequence was correctly folded with respect to its central COL2 and carboxylterminal COL3 domains. Between them, in the NC3 domain, a second coiled-coil sequence was found, and this was suggested to function as a second association region. The second coiled-coil sequence was found to be conserved in the two other type XIII collagen-like molecules as well. To obtain precise information about the location and level of type XIII collagen expression, a reporter mouse line synthesizing a recombinant protein with the cytoplasmic and transmembrane portions of type XIII collagen linked in-frame with the β-galactosidase enzyme was generated. The reporter mice showed high expression of type XIII collagen at neuromuscular junctions and in the periosteum of bone. Interestingly, the growth of the reporter mice was reduced at puberty. Their long bones showed a decreased diameter and impaired mechanical properties. In addition, their peripheral nerves showed areas of detachment from muscle cells at neuromuscular junctions. These results provide further evidence for the role of type XIII collagen in cell adhesion. They also show the importance of proper adhesion conducted by type XIII collagen in signaling between the extracellular matrix and cells and in the cellular response.

Abstract Overlapping genomic clones coding for the α1 chain of mouse type XV collagen (Col15a1) were isolated. The gene was found to be 110 kb in length and to contain 40 exons. Analysis of the proximal 5'-flanking region showed properties characteristic of a housekeeping gene promoter, and functional analysis identified cis-acting elements for both positive and negative regulation of Col15a1 gene expression. The general exon-intron pattern of the mouse Col15a1 gene was found to be highly similar to that of its human homologue, and comparison of 5'-flanking sequences indicated four conserved domains. The genomic area encoding the end of the N-terminal non-collagenous domain nevertheless showed marked divergence from the human form. Due to the lack of two exons coding for the N-terminal collagenous domain and a codon divergence in one exon, the mouse β1(XV) chain contains seven collagenous domains whereas the human equivalent contains nine. In order to understand the biological role of this protein, a null mutation in the Col15a1 gene was introduced into the germ line of mice. Despite the wide tissue distribution of type XV collagen, the null mice developed and reproduced normally and were indistinguishable from their wild-type littermates. After three months of age, however, microscopic analysis revealed progressive histological changes characteristic of myopathic disorder, and treadmill exercise resulted in greater skeletal muscle injury than in the wild-type mice. Irrespective of potential anti-angiogenic properties of type XV collagen-derived endostatin, the number of vessels appeared normal. Nevertheless, ultrastructural analyses revealed markedly abnormal capillaries and endothelial cell degeneration in the heart and skeletal muscle. Perfused hearts showed a diminished inotropic response, and exercise resulted in cardiac injury, changes that mimic early or mild heart disease. Thus type XV collagen appears to function as a necessary structural component for stabilizing cells with surrounding connective tissue in skeletal muscle cells and microvessels. Mice lacking the type XV collagen homologue, type XVIII collagen, showed delayed regression of blood vessels in the vitreous body of the eye and abnormal outgrowth of the retinal vessels. This suggests that collagen XVIII plays a role in regulating vascular development in the eye. Moreover, type XVIII collagen was found to be important at the surface between the inner limiting membrane and the collagen fibrils of the vitreous body. Col18a1 deficient mice serve as an animal model for the recessively inherited Knobloch syndrome, characterized by various eye abnormalities and occipital encephalocele. The results presented in this thesis indicate diverse biological roles for the closely related collagen types XV and XVIII.

Master of Science / Department of Kinesiology / Timothy I. Musch / Dietary supplementation with omega-3 polyunsaturated fatty acids (PUFAs) containing docosahexaenoic (DHA) and eicosapentaenoic acid (EPA) has been demonstrated to produce advantageous effects on vascular function. Specifically, PUFA supplementation has resulted in enhanced brachial artery blood flow (Q), dilation, and vascular conductance (VC) during rhythmic handgrip exercise. The effects of fish oils (FO) on skeletal muscle blood flow (Qm) during dynamic whole body exercise, however, remain unknown. PURPOSE: To test our hypothesis that 6 weeks of dietary FO supplementation with DHA and EPA enhances regional Qm and VC to the hindlimb musculature during submaximal treadmill exercise. METHODS: Following 6 weeks of dietary supplementation with safflower oil (SO) (control; n = 9) or FO (n = 8), heart rate (HR), mean arterial pressure (MAP), and Q[subscript]m to the hindlimb were measured at rest and during submaximal treadmill exercise (20 m/min, 10%, ~65% VO[subscript]2max) via radiolabeled microspheres in adult male Sprague-Dawley rats. RESULTS: HR and MAP were not different between SO and FO at rest or exercise (P<0.05). Q[subscript]m and VC were not different between SO and FO at rest. During exercise, FO exhibited greater Q[subscript]m in 8 of the 28 muscle parts measured as well as greater VC in 11 of the 28 muscle parts measured. Additionally, FO exhibited greater (Q)[subscript] m (158[plus or minus]9) and VC (1.156[plus or minus]0.066) to the total hindlimb musculature than SO (128[plus or minus]10 ml/min/100g, 0.918[plus or minus]0.077 ml/min/100g/mmHg) (P<0.05). CONCLUSION: These results demonstrate that 6 weeks of dietary FO supplementation with DHA and EPA results in enhanced Q[subscript]m and VC to the hindlimb during submaximal exercise. Thus, supplementation with DHA and EPA may have therapeutic effects on oxygen delivery and vascular function in patients with impaired vascular function and exercise tolerance (i.e., congestive heart failure, diabetes).

La dystrophie FacioScapuloHumérale (FSHD), décrite pour la première fois en 1885 par Landouzy Dejerine, est la première dystrophie musculaire de l’adulte en France affectant entre 4000 et 5000 personnes. La destruction progressive des fibres musculaires entraîne une atrophie et une faiblesse musculaires s’aggravant progressivement, avec cependant une grande variabilité intra-familiale du degré des atteintes. Une caractéristique de l’atteinte musculaire est généralement son asymétrie. Les premières manifestations concernent souvent les muscles du visage, les muscles de l’omoplate et des muscles perihuméraux. En progressant la pathologie va toucher d’autres territoires musculaires. Dans environ 10 à 15 % des cas, à un stade évolué, les patients sont contraints d'utiliser un fauteuil roulant. En dépit d’avancées majeures dans la compréhension du locus morbide, les mécanismes exacts responsables des défauts musculaires de la FSHD ne sont toujours pas compris et il n’existe aucune thérapie. Toutefois, il existe de plus en plus de données qui permettent une implication probable du stress oxydant dans cette pathologie. L’hypothèse selon laquelle les réponses antioxydantes sont altérées dans la FSHD s’appuie sur des dérégulations d’enzymes impliqués dans le stress oxydant. Une étude prospective réalisée sur des patients FSHD et des volontaires sains nous a ainsi permis de mettre en évidence une corrélation entre le stress oxydant systémique et musculaire et leurs déficits fonctionnels musculaires. Ces données nous ont conduit à la mise en place d’un essai clinique randomisé, contrôlé, en double aveugle contre placébo, visant à évaluer les effets d’une supplémentation en antioxydants chez 54 patients atteints de FSHD pendant 17 semaines. Cet essai a ainsi permis de montrer une augmentation significative de la force et l’endurance des quadriceps corrélée à une diminution du stress oxydant et une augmentation des défenses antioxydantes chez les patients atteints de FSHD. De nombreuses caractéristiques de la FSHD pourraient être causées et/ou exacerbées par des perturbations de la production des espèces radicalaires ou une réponse non adaptée à cette production. Aussi le premier objectif de ma thèse est de mener une étude comparative des profils d’oxygénation par spectroscopie dans le proche infrarouge de patients atteints de FSHD et sains. Le second objectif est d’évaluer l’effet de la supplémentation en antioxydant sur le volume des quadriceps par IRM et leur qualité musculaire déterminée par le ratio Force/Volume musculaire du quadriceps et d’évaluer les corrélations entre ces variables, la force et le stress oxydant. Les données obtenues ont permis de montrer une réduction de la capacité oxydative lors d’une contraction isométrique volontaire des quadriceps et ont permis d’étudier l’effet de la supplémentation sur les volumes et la qualité musculaire des quadriceps. Ces augmentations sont associées non seulement à une augmentation de la force des quadriceps mais aussi à une diminution du stress oxydant et une augmentation des défenses antioxydantes. L’ensemble de ces données montrent que le stress oxydant pourrait jouer un rôle important dans la FSHD et qu’une approche antioxydante semble adaptée à cette pathologie. Des analyses plus fines sur l’action des espèces réactives de l’oxygène (ROS) et leurs sources pourraient contribuer à une meilleure compréhension des bases physiopathologiques de la FSHD. / Facioscapulohumeral muscular dystrophy (FSHD), first described in 1885 by Landouzy Dejerine, is the most common inherited skeletal muscle disease of adult life affecting 4000 to 5000 persons in France. Progressive evolution of the disease leads to progressive weakness and atrophy of muscle fibers associated to a wide variability. The pattern of muscle weakness is often asymmetrical and the rate and extent of progression may vary considerably with sudden periods of unexplained rapid disease progression. This muscle disorder is characterized by progressive muscle weakness, beginning with facial muscles and the shoulder girdle, followed by the pelvic girdle and the muscles of the lower extremities. In 10 to 15% of cases, patients need to use a wheelchair. Despite major progress in the understanding of the genetic basis of FSHD, the exact mechanisms that lead to FSHD defects are not completely understood and no curative treatment is available. However, there is growing evidence that oxidative stress may contribute to FSHD pathology. The hypothesis that oxidative stress responses might be specifically altered in FSHD is supported by the deregulation of enzymes involved in oxidative stress.A prospective study realized with FSHD patients and healthy subjects unrevealed the correlation between systemic and muscular oxidative stress and functional muscle defects. Based on these data, we organized a randomized, double-blind, placebo-controlled pilot clinical trial in order to evaluate the effects of 17 weeks antioxidant supplementation in 54 FSHD patients. This clinical trial demonstrates a significant increase in muscle force and quadriceps endurance correlated to a decrease in oxidative stress and an increase in antioxidant defense in FSHD patientsFurthermore, many FSHD features may be caused or exacerbated by perturbations in the production of free radicals or inappropriate response to such stressors. Therefore the first objective was planned to investigate muscle oxygenation patterns during and after a MVCQ by near-infrared diffuse optical spectroscopy (NIRS). The second objective is to evaluate the effect of antioxidant supplementation on quadriceps volumes by IRM and determine the muscle quality using Strength/ Volume ratio of quadriceps muscles and correlate this variables with force and oxidative stress parameters.The major findings of this study show a significant decrease in oxidative capacity during voluntary isometric contraction in quadriceps and demonstrate the effect of supplementation on muscle volume and quality. Indeed, vitamin E, vitamin C, zinc and selenium supplementation improves muscle volume and quality of both quadriceps by enhancing the antioxidant defences and reducing oxidative stress.This increase are associated to increase in strength and decrease in oxidative stress and increase in antioxidant defences. Taken together, we show that oxidative stress plays an important role in FSHD and that an anti-oxidant strategy adapted to the FSHD-specific “oxidative stress” may be a relevant therapeutic approach for these patients. Further analyses of ROS production and sources could contribute to a better understanding of the pathophysiological mechanisms implicated in FSHD.

La qualité des carcasses et des viandes bovines dépend de l’équilibre entre les masses musculaires et adipeuses qui conditionnent le poids de carcasse et son rendement (composition en muscle et en gras), mais aussi la qualité sensorielle de la viande (tendreté, jutosité et flaveur). Comprendre comment contrôler le rapport des masses de muscle relativement à celles des tissus adipeux (TA) représente donc un enjeu majeur pour les filières de viande bovine. Ce rapport dépend du nombre et du volume des cellules musculaires et adipeuses. Ces propriétés sont sous le contrôle d’événements cellulaires se mettant en place précocement chez le bovin puisque le nombre de cellules musculaires est fixé dès l’âge 180 jours post-conception (jpc) chez le fœtus. Des analyses de l’évolution des protéomes de ces deux tissus, au cours de la vie fœtale ont produit des données originales mais insuffisantes. En outre, il n’est pas toujours aisé d’extraire ou de générer une information biologique pertinente à partir d’expérimentations de génomique. Ceci est particulièrement vrai chez les ruminants, car ils sont peu annotés dans les bases de données et peu de ressources bioinformatiques leur sont dédiées. Dans ce contexte, notre objectif était de concevoir un serveur web « tout en un » permettant une fouille des données de génomique chez le bovin afin d’améliorer les connaissances sur les mécanismes associés à la croissance par hyperplasie et par hypertrophie des tissus musculaire et adipeux. Aussi, nous avons organisé notre travail de thèse en deux axes. Un outil d’analyse de données de génomique, dédié aux ruminants (bovin, ovin et caprin) nommé ProteINSIDE (www.proteinside.org) a été développé. En une seule requête, il synthétise l'information biologique stockée dans les bases de données publiques ou fournie par les annotations fonctionnelles issues de l’ontologie des gènes. Il prédit aussi les protéines qui sont sécrétées (sécrétome des tissus) et qui interviennent dans la signalisation entre les cellules ou tissus. Il lie les protéines selon leurs interactions moléculaires afin d’identifier et de visualiser celles qui contribuent à un même processus biologique et celles qui sont centrales à un processus biologique. ProteINSIDE a été testé avec des jeux de données de 1000 protéines par espèce et a été comparé avec succès à DAVID, BioMyn et AgBase, conçus pour la recherche d'information et l'annotation, ainsi qu'à PrediSi et Phobius qui prédisent les protéines sécrétées. ProteINSIDE a été appliqué à l’analyse des protéomes des tissus musculaires et adipeux. Une première analyse des données relatives à l’ontogenèse des tissus, a révélé des liens entre des protéines présentes dans les deux tissus fœtaux et des protéines impliquées dans les processus d’autophagie. Dans une seconde étude, nous avons décrit les protéomes des deux tissus à 140 jpc. Nous avons identifié 514 protéines musculaires et 752 protéines adipeuses, dont 346 communes. Ces protéines interviennent par exemple dans la régulation négative de l’apoptose, dans les processus d’autophagie, dans la régulation de la prolifération cellulaire et dans la voie de signalisation Wnt. Nous avons identifié 47 et 93 protéines potentiellement sécrétées par le muscle et le TA, dont 24 communes. L’intégration des connaissances sur les protéines sécrétées avec celles disponibles pour le « surfaceome » a suggéré des protéines qui participeraient au dialogue muscle-TA. Nous avons donc produit un serveur web pour la fouille de données de génomique non seulement chez le bovin, l’ovin, le caprin, mais aussi chez l’homme, le rat et la souris. Ce type de serveur devrait être particulièrement utile à la communauté scientifique. Son application a conduit à la production de connaissances nouvelles et d’hypothèses de travail pour la compréhension des mécanismes de régulation de la croissance fœtale du muscle squelettique et du tissu adipeux. / The quality of carcasses and meats depends on the balance between muscle and adipose tissue (AT) masses that determine carcass weight and performance (muscle and fat composition), but also the sensory quality of the meat (tenderness, juiciness and flavor). Understanding how to control the ratio of muscle mass relative to AT mass represents a major challenge for beef producers. The balance between these masses depends on the number and volume of muscle and AT cells. These cellular events are taking place at the early steps of fetal period in cattle, as the total number of muscle cells is fixed at 180 days post-conception (dpc) in the fetus. The analysis of the evolution of these two proteome tissues during fetal life produced original but insufficient data. In addition, it is not always easy to extract or generate relevant biological information from genomic experiments. This is particularly true in ruminant species because they are not annotated in databases and few bioinformatic resources are dedicated to them. In this context, our objective was to design an “all in one” web service to analyze genomic data in cattle in order to improve knowledge of the mechanisms involved in fetal muscle and AT growth. Thus, we have organized our thesis in two axes. We developed a genomic data analysis tool, dedicated to ruminant species (cattle, sheep and goat) and named ProteINSIDE (www.proteinside.org). In a single query, this tool synthesizes the biological information stored in public databases or provided by functional annotations from gene ontology. It also predicts proteins that are secreted (tissue secretome) and which are involved in signaling between cells or tissues. It links proteins according to their molecular interactions to identify and visualize those that contribute to the same biological processes and those that are central to a biological process. ProteINSIDE was tested with data sets of 1000 proteins by species and has been successfully compared with DAVID, BioMyn, and AgBase (designed for information retrieval and annotation), as well as PrediSi and Phobius (that predict proteins secreted). We applied ProteINSIDE to the proteome analysis of muscle and AT. A first analysis of data on the ontogenesis of the tissue revealed links between proteins of both fetal tissues and proteins involved in autophagy processes. In a second study, we constructed and described the bovine proteomes of both tissues at 140 dpc. We identified 514 muscle protein and 752 AT proteins, including 346 commons proteins. As an example, these proteins are involved in the negative regulation of apoptosis, in autophagy processes, in the regulation of cell proliferation, and in the Wnt signaling pathway. We identified 47 and 93 potentially secreted proteins by muscle and TA, including 24 commons proteins. The integration of knowledges about the secreted proteins with those available for the “surfaceome” suggested proteins which could participate in the cross-talk between muscle and AT. Thus, we produced a web server to mine genomic data from bovine, sheep, and goat species, but also from human, rat and mice species. This type of server should be particularly useful to the scientific community. Its implementation has led to the production of new knowledge and working hypotheses for the understanding of the mechanisms which regulate fetal growth of muscle and AT.

Cellulose nanowhiskers (CNWs) are high aspect ratio rod-like nanoparticles with diameters on the order of a few nanometers. For the very first time CNWs are demonstrated as a useful material for guided tissue engineering. Due to their nanoscale dimensions and high aspect ratio, highly oriented spin coated surfaces of CNWs are shown to direct the morphology and terminal differentiation of myoblasts, allowing the culture of skeletal muscle-like tissue with a more physiologically relevant structure.CNWs are prepared from cellulose extracted from the tunicate Ascidiella sp. using acid hydrolysis to prepare high aspect ratio particles with diameters of approximately 5 to 6 nm. A spin coating method is used to prepare sparsely adsorbed sub-monolayers of CNWs with a high degree of relative orientation. The surfaces have a mean feature height of only 5.5 nm and the degree of CNW adsorption and orientation is modulated by altering the preparation procedure. When C2C12 myoblasts are seeded to the surfaces, the cells adopt highly oriented morphologies induced by the CNWs via contact guidance. This is a demonstration of contact guidance on some of the smallest topographical features ever reported. Furthermore, the highly oriented CNWs promote fusion and terminal differentiation of the myoblasts to form multinucleated myotubes with a striking degree of parallel orientation.CNW surfaces are also shown to support the adhesion and spreading of human mesenchymal stem cells, inducing the adoption of highly oriented cell morphologies. The ability of hMSCs to undergo cell fusion with C2C12 myotubes highlights the great potential for tissue engineering human skeletal muscle, using CNWs to direct the structure of the tissue. The bioactivity and low cytotoxicity of CNWs, coupled with their low cost and simple production procedure, indicates that CNWs will be a useful material for tissue engineering and regenerative medicine.

No description available.

Skeletal muscle atrophy is a debilitating condition caused by pathological conditions including cancer cachexia, disuse and denervation. Disuse atrophy is characterized by reduction in fiber size, fiber-type change and induction of markers of atrophy such as MuRF1 and Fn14. Recent studies have focused on understanding the fundamental role of signalling pathways and the proteolytic system in response to muscle atrophy. Unfortunately the exact mechanisms behind atrophy remain poorly understood. I recently demonstrated that cIAP1 and/or cIAP2 proteins are critical regulators of NF-kB activation, which has been shown to be involved in skeletal muscle atrophy. Here, I used genetic and pharmacological means to investigate the role of cIAP1 in a denervation-induced skeletal muscle atrophy model. Interestingly, I found that upon denervation loss of cIAP1 rescues muscle fiber size, prevents fiber-type changing and inhibits the expression of MuRF1 and Fn14. Moreover, treatment of mice with Smac mimetic compounds (SMC), a novel class of small molecule IAP antagonists, showed successful knockdown of cIAP1 in muscle and protects against denervation-induced muscle atrophy. Taken together, these data reveal that cIAP1 is both a novel mediator of skeletal muscle atrophy and an important therapeutic target.

Over the past decade several converging lines of evidence have highlighted the importance of post-transcriptional events in skeletal muscle. This level of regulation is controlled by multi-functional RNA-binding proteins and trans-acting factors. In fact, several RNA-binding proteins are implicated in neuromuscular disorders including myotonic dystrophy type I, spinal muscular atrophy and amyotrophic lateral sclerosis. Therefore, it is necessary to examine the impact of RNA-binding proteins during skeletal muscle development and plasticity in order to understand the consequences linked to their misregulation in disease. Here, we focused on the RNA-binding protein Staufen1, which assumes multiple roles in both skeletal muscle and neurons. We previously demonstrated that Staufen1 is regulated during myogenic differentiation and that its expression is increased in denervated and in myotonic dystrophy type I skeletal muscles. The increased expression of Staufen1 initially appeared beneficial for DM1 since further elevating Staufen1 levels rescued key hallmarks of the disease. However, based on the multi-functional nature of Staufen1, we hypothesized that Staufen1 acts as a disease modifier in DM1. To test this, we investigated the roles of Staufen1 in skeletal muscle biology and their implications for disease. Our data demonstrated that Staufen1 is required during the early stages of muscle development, however its expression must remain low in postnatal skeletal muscle. Interestingly, the overexpression of Staufen1 impaired myogenesis through the regulation of c-myc translation. Since the function of c-myc in oncogenesis is well described, we investigated the role of Staufen1 in cancer biology. In particular, we determined novel functions of Staufen1 in rhabdomyosarcoma tumorigenesis, thus providing the first direct evidence for Staufen1’s involvement in cancer. Moreover, based on Staufen1’s role in myogenic differentiation and in myotonic dystrophy type I, we generated muscle-specific transgenic mice to examine the impact of sustained Staufen1 expression in postnatal skeletal muscle. Staufen1 transgenic mice developed a myopathy characterized by histological and functional abnormalities via atrogene induction and the regulation of PTEN mRNAs. In parallel, we further investigated Staufen1-regulated alternative splicing and our data demonstrated that Staufen1 regulates multiple alternative splicing events in normal and myotonic dystrophy type I skeletal muscles, both beneficial and detrimental for the pathology. Collectively, these findings uncover several novel functions of Staufen1 in skeletal muscle biology and highlight Staufen1’s role as a disease modifier in DM1.