Multiomics analysis of the mdx/mTR mouse model of Duchenne muscular dystrophy.

PURPOSE/AIM: Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease characterized by extensive muscle weakness. Patients with DMD lack a functional dystrophin protein, which transmits force and organizes the cytoskeleton of skeletal muscle. Multiomic studies have been proposed as a way to obtain novel insight about disease processes from preclinical models, and we used this approach to study pathological changes in dystrophic muscles. MATERIALS AND METHODS: We evaluated hindlimb muscles of male mdx/mTR mice, which lack a functional dystrophin protein and have deficits in satellite cell abundance and proliferative capacity. Wild type (WT) C57BL/6 J mice served as controls. Muscle fiber contractility was measured, along with changes in the transcriptome using RNA sequencing, and in the proteome, metabolome, and lipidome using mass spectrometry. RESULTS: While mdx/mTR mice displayed gross pathological changes and continued cycles of degeneration and regeneration, we found no differences in permeabilized fiber contractility between strains. However, there were numerous changes in the transcriptome and proteome related to protein balance, contractile elements, extracellular matrix, and metabolism. There was only a 53% agreement in fold-change data between the proteome and transcriptome. Numerous changes in markers of skeletal muscle metabolism were observed, with dystrophic muscles exhibiting elevated glycolytic metabolites such as 6-phosphoglycerate, fructose-6-phosphate and glucose-6-phosphate, fructose bisphosphate, phosphorylated hexoses, and phosphoenolpyruvate. CONCLUSIONS: These findings highlight the utility of multiomics in studying muscle disease, and provide additional insight into the pathological changes in dystrophic muscles that might help to indirectly guide evidence-based nutritional or exercise prescription in DMD patients.

Gender-specific hip strength disparities correlate with injury patterns in NCAA men's and women's soccer players.

BACKGROUND: In National Collegiate Athletic Association (NCAA) soccer athletes, men have higher rates of hip and groin strains, whereas women have higher rates of knee ligament injuries. Strength imbalances of the hip and thigh, specifically in agonist-antagonist muscles, are known risk factors for these injuries. OBJECTIVE: To perform hip and thigh strength assessments in NCAA soccer players to evaluate for differences between genders and correlations with gender-specific injury patterns. DESIGN: With a handheld dynamometer, weight-normalized isometric strength of six muscle groups (hip abductors, hip adductors, hip flexors, hip extensors, knee flexors, knee extensors) was calculated in NCAA soccer players. The strength ratio of each agonist-antagonist muscle was also calculated (hip abductors/adductors, hip flexors/extensors, knee extensors/flexors). PARTICIPANTS: Thirty-six NCAA soccer players (18 men, 18 women) from a single NCAA Division III institution. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Weight-normalized strength of six muscle groups and their agonist-antagonist strength ratios were compared between genders using linear mixed-effects models. RESULTS: Compared with male players, female players had decreased weight-normalized strength for hip abduction (0.170 vs. 0.204, p = .012) and hip extension (0.172 vs. 0.211, p = .021). Otherwise, weight-normalized strength was similar between genders. When comparing agonist-antagonist strength ratios, there was a significant difference between female and male players for hip flexion:extension (1.70 vs. 1.35, p = .008), whereas the hip abduction: adduction ratio did not reach statistical significance (1.45 vs. 1.62, p = .080). CONCLUSIONS: NCAA male and female soccer players had different hip strength profiles that fit their injury patterns. Male NCAA soccer players have higher rates of hip and groin strains, and men in the cohort had strength ratios that were deficient in the hip flexors and adductors compared with women. Female NCAA soccer players have higher rates of knee sprains and anterior cruciate ligament tears, and women in the cohort had strength ratios that were deficient in the hip abductors and extensors, which function to stabilize the knee. These strength disparities could be the focus of future gender-specific soccer injury prevention programs.

p38 MAPK signaling in postnatal tendon growth and remodeling.

Tendon is a dynamic tissue whose structure and function is influenced by mechanical loading, but little is known about the fundamental mechanisms that regulate tendon growth and remodeling in vivo. Data from cultured tendon fibroblasts indicated that the p38 MAPK pathway plays an important role in tendon fibroblast proliferation and collagen synthesis in vitro. To gain greater insight into the mechanisms of tendon growth, and explore the role of p38 MAPK signaling in this process, we tested the hypotheses that inducing plantaris tendon growth through the ablation of the synergist Achilles tendon would result in rapid expansion of a neotendon matrix surrounding the original tendon, and that treatment with the p38 MAPK inhibitor SB203580 would prevent this growth. Rats were treated with vehicle or SB203580, and subjected to synergist ablation by bilateral tenectomy of the Achilles tendon. Changes in histological and biochemical properties of plantaris tendons were analyzed 3, 7, or 28 days after overload, and comparisons were made to non-overloaded animals. By 28 days after overload, tendon mass had increased by 30% compared to non-overloaded samples, and cross-sectional area (CSA) increased by around 50%, with most of the change occurring in the neotendon. The expansion in CSA initially occurred through the synthesis of a hyaluronic acid rich matrix that was progressively replaced with mature collagen. Pericytes were present in areas of active tendon growth, but never in the original tendon ECM. Inhibition of p38 MAPK resulted in a profound decrease in IL6 expression, and had a modest effect on the expression of other ECM and cell proliferation genes, but had a negligible impact on overall tendon growth. The combined results from this study provided novel insights into tendon mechanobiology, and suggest that p38 MAPK signaling does not appear to be necessary for tendon growth in vivo.