RESUMEN
BACKGROUND: Duchenne muscular dystrophy (DMD) is an incurable neuromuscular disease leading to progressive skeletal muscle weakness and fatigue. Cell transplantation in murine models has shown promise in supplementing the lack of the dystrophin protein in DMD muscles. However, the establishment of novel, long-term, relevant methods is needed to assess its efficiency on the DMD motor function. By applying newly developed methods, this study aimed to evaluate the functional and molecular effects of cell therapy-mediated dystrophin supplementation on DMD muscles. METHODS: Dystrophin was supplemented in the gastrocnemius of a 5-week-old immunodeficient DMD mouse model (Dmd-null/NSG) by intramuscular xenotransplantation of healthy human immortalized myoblasts (Hu5/KD3). A long-term time-course comparative study was conducted between wild-type, untreated DMD, and dystrophin supplemented-DMD mouse muscle functions and histology. A novel GO-ATeam2 transgenic DMD mouse model was also generated to assess in vivo real-time ATP levels in gastrocnemius muscles during repeated contractions. RESULTS: We found that 10.6% dystrophin supplementation in DMD muscles was sufficient to prevent low values of gastrocnemius maximal isometric contraction torque (MCT) at rest, while muscle fatigue tolerance, assessed by MCT decline after treadmill running, was fully ameliorated in 21-week-old transplanted mice. None of the dystrophin-supplemented fibers were positive for muscle damage markers after treadmill running, with 85.4% demonstrating the utilization of oxidative metabolism. Furthermore, ATP levels in response to repeated muscle contractions tended to improve, and mitochondrial activity was significantly enhanced in dystrophin supplemented-fibers. CONCLUSIONS: Cell therapy-mediated dystrophin supplementation efficiently improved DMD muscle functions, as evaluated using newly developed evaluation methods. The enhanced muscle fatigue tolerance in 21-week-old mice was associated with the preferential regeneration of damage-resistant and oxidative fibers, highlighting increased mitochondrial activity, after cell transplantation. These findings significantly contribute to a more in-depth understanding of DMD pathogenesis.
Asunto(s)
Modelos Animales de Enfermedad , Distrofina , Fatiga Muscular , Músculo Esquelético , Distrofia Muscular de Duchenne , Animales , Distrofia Muscular de Duchenne/terapia , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología , Distrofina/genética , Distrofina/metabolismo , Ratones , Músculo Esquelético/metabolismo , Humanos , Mioblastos/metabolismo , Ratones Endogámicos mdx , Masculino , Contracción Muscular , Trasplante de Células/métodosRESUMEN
INTRODUCTION: High heeled shoes have long been worn in society and they are known to cause biomechanical imbalances to not only the foot, but the whole musculoskeletal system. This study aims to show the detailed changes that happen to the shape of the transverse arch of the foot in high heels, using two different inclination degrees. METHODS: 68 women participated in this study. Two custom-made high heels were made with inclinations of 15 degrees and 30 degrees (cm). A weight-bearing ultrasound was used to assess the coronal view of the transverse arch in standing. ANOVA and Tuckey tests were used to compare the results between 0 degrees, 15 degrees and 30 degrees inclinations. RESULTS: The transverse arch height was slightly increased as the heel height increased (0DI-15DI: p = 0.5852 / 15DI-30DI: p = 0.395 / 0DI-30DI: p = 0.0593). The transverse arch length (0DI-15DI: p = 0.0486 / 15DI-30DI: p = 0.0004 / 0DI-30DI: p = 0.1105) and the area under the metatarsal heads (0DI-15DI: p = 0.0422 / 15DI-30DI: p = 0.0180 / 0DI-30DI: p = 0.9463) significantly decreased as the heel height increased. DISCUSSION: The main changes were viewed in the 30 degrees inclinations compared to 0 degrees inclination. When the toes are dorsiflexed in high heels, it stimulates the Windlass mechanism which in turn stiffens the plantar fascia and adducts the metatarsal heads, while the soft tissues shrink in response to loads. CONCLUSION: High heels affected the shape of the transverse arch even in short term standing, and these effects increased as the height of the heel increased.