Duchenne and Becker muscular dystrophy: Cellular mechanisms, image analysis, and computational models: A review.

The muscle is the principal tissue that is capable to transform potential energy into kinetic energy. This process is due to the transformation of chemical energy into mechanical energy to enhance the movements and all the daily activities. However, muscular tissues can be affected by some pathologies associated with genetic alterations that affect the expression of proteins. As the muscle is a highly organized structure in which most of the signaling pathways and proteins are related to one another, pathologies may overlap. Duchenne muscular dystrophy (DMD) is one of the most severe muscle pathologies triggering degeneration and muscle necrosis. Several mathematical models have been developed to predict muscle response to different scenarios and pathologies. The aim of this review is to describe DMD and Becker muscular dystrophy in terms of cellular behavior and molecular disorders and to present an overview of the computational models implemented to understand muscle behavior with the aim of improving regenerative therapy.

Whole-Body MRI in Limb Girdle Muscular Dystrophy Type R1/2A: Correlation With Clinical Scores.

INTRODUCTION/AIM: The most common limb girdle muscular dystrophy (LGMD) worldwide is LGMD type R1 (LGMDR1). The aim of this study was to correlate the MRI findings with functional scores and to describe the whole-body MRI (WBMRI) pattern in a LGMDR1 Brazilian cohort. METHODS: LGMDR1 patients under follow-up in three centers were referred for the study. Clinical data were collected and a functional evaluation was performed, consisting of Gardner-Medwin and Walton (GMW) and Brooke scales. All patients underwent a WBMRI study (1.5T) with axial T1 and STIR images. Fifty-one muscles were semiquantitatively assessed regarding fatty infiltration and muscle edema. RESULTS: The study group consisted of 18 patients. The highest fatty infiltration scores involved the serratus anterior, biceps femoris long head, adductor magnus, and lumbar erector spinae. There was a latero-medial and caudo-cranial descending gradient of involvement of the paravertebral muscles, with erector spinae being significantly more affected than the transversospinalis muscles (p < 0.05). A striped appearance that has been dubbed the "pseudocollagen sign" was present in 72% of the patients. There was a positive correlation between the MRI score and GMW (Rho:0.83) and Brooke (Rho:0.53) scores. DISCUSSION: WBMRI in LGMDR1 allows a global patient evaluation including involvement of the paraspinal muscles, usually an underestimated feature in the clinical and imaging study of myopathies. Knowledge of the WBMRI pattern of LGMDR1 involvement can be useful in the diagnostic approach and in future studies to identify the best target muscles to serve as outcome measures in clinical trials.

Expression of CTGF/CCN2 in response to LPA is stimulated by fibrotic extracellular matrix via the integrin/FAK axis.

Fibrosis is a common feature of several chronic diseases and is characterized by exacerbated accumulation of ECM. An understanding of the cellular and molecular mechanisms involved in the development of this condition is crucial for designing efficient treatments for those pathologies. Connective tissue growth factor (CTGF/CCN2) is a pleiotropic protein with strong profibrotic activity. In this report, we present experimental evidence showing that ECM stimulates the synthesis of CTGF in response to lysophosphatidic acid (LPA).The integrin/focal adhesion kinase (FAK) signaling pathway mediates this effect, since CTGF expression is abolished by the use of the Arg-Gly-Asp-Ser peptide and also by an inhibitor of FAK autophosphorylation at tyrosine 397. Cilengitide, a specific inhibitor of αv integrins, inhibits the expression of CTGF mediated by LPA or transforming growth factor ß1. We show that ECM obtained from decellularized myofibroblast cultures or derived from activated fibroblasts from muscles of the Duchenne muscular dystrophy mouse model ( mdx) induces the expression of CTGF. This effect is dependent on FAK phosphorylation in response to its activation by integrin. We also found that the fibrotic ECM inhibits skeletal muscle differentiation. This novel regulatory mechanism of CTGF expression could be acting as a positive profibrotic feedback between the ECM and CTGF, revealing a novel concept in the control of fibrosis under chronic damage.