RESUMO
BACKGROUND: Children with spastic cerebral palsy (CP) have damage to the corticospinal tracts that are responsible for selective motor control (SMC). Force, velocity and timing of joint movement are related biomechanical features controlled by the corticospinal tracts (CSTs) that are important for skilled movement. RESEARCH QUESTION: Does SMC influence knee joint biomechanics in spastic CP? METHODS: In this prospective study, relationships between SMC and knee biomechanics (peak torque, total work, average power) across a range of velocities (0-300â¯deg/s) were assessed using an isokinetic dynamometer in 23 children with spastic CP. SMC was assessed using Selective Control Assessment of the Lower Extremity (SCALE). Logistic and linear regression models were used to evaluate relationships between SCALE and biomechanical measures. RESULTS: The ability to produce knee torque diminished with increasing velocity for both Low (0-4 points) and High (5-10 points) SCALE limb score groups (p < 0.01). More knees in the High group produced extension torque at 300â¯deg/s (p < 0.05) and flexion torque at 30, 90,180, 240 and 300â¯deg/s (p < 0.05). The ability to produce torque markedly decreased above 180â¯deg/s for Low group flexion. For knees that produced torque, significant positive correlations between SCALE limb scores and joint torque (0 and 120â¯deg/s), work (120â¯deg/s) and power (120â¯deg/s) were found (p < 0.05). Greater knee torque, work and power for the High group was found for the extensors at most velocities and the flexors for up to 120â¯deg/s (p < 0.05). Few Low group participants generated knee flexor torque above 120â¯deg/s limiting comparisons. SIGNIFICANCE: Biomechanical impairments found for children with low SMC are concerning as skilled movements during gait, play and sport activities occur at high velocities. Differences in SMC should be considered when designing individualized assessments and interventions.
RESUMO
We developed an on-slide decellularization approach to generate acellular extracellular matrix (ECM) myoscaffolds that can be repopulated with various cell types to interrogate cell-ECM interactions. Using this platform, we investigated whether fibrotic ECM scarring affected human skeletal muscle progenitor cell (SMPC) functions that are essential for myoregeneration. SMPCs exhibited robust adhesion, motility, and differentiation on healthy muscle-derived myoscaffolds. All SPMC interactions with fibrotic myoscaffolds from dystrophic muscle were severely blunted including reduced motility rate and migration. Furthermore, SMPCs were unable to remodel laminin dense fibrotic scars within diseased myoscaffolds. Proteomics and structural analysis revealed that excessive collagen deposition alone is not pathological, and can be compensatory, as revealed by overexpression of sarcospan and its associated ECM receptors in dystrophic muscle. Our in vivo data also supported that ECM remodeling is important for SMPC engraftment and that fibrotic scars may represent one barrier to efficient cell therapy.
RESUMO
BACKGROUND: The dystrophin-glycoprotein complex (DGC) is a critical adhesion complex of the muscle cell membrane, providing a mechanical link between the extracellular matrix (ECM) and the cortical cytoskeleton that stabilizes the sarcolemma during repeated muscle contractions. One integral component of the DGC is the transmembrane protein, sarcospan (SSPN). Overexpression of SSPN in the skeletal muscle of mdx mice (murine model of DMD) restores muscle fiber attachment to the ECM in part through an associated increase in utrophin and integrin adhesion complexes at the cell membrane, protecting the muscle from contraction-induced injury. In this study, we utilized transcriptomic and ECM protein-optimized proteomics data sets from wild-type, mdx, and mdx transgenic (mdxTG) skeletal muscle tissues to identify pathways and proteins driving the compensatory action of SSPN overexpression. METHODS: The tibialis anterior and quadriceps muscles were isolated from wild-type, mdx, and mdxTG mice and subjected to bulk RNA-Seq and global proteomics analysis using methods to enhance capture of ECM proteins. Data sets were further analyzed through the ingenuity pathway analysis (QIAGEN) and integrative gene set enrichment to identify candidate networks, signaling pathways, and upstream regulators. RESULTS: Through our multi-omics approach, we identified 3 classes of differentially expressed genes and proteins in mdxTG muscle, including those that were (1) unrestored (significantly different from wild type, but not from mdx), (2) restored (significantly different from mdx, but not from wild type), and (3) compensatory (significantly different from both wild type and mdx). We identified signaling pathways that may contribute to the rescue phenotype, most notably cytoskeleton and ECM organization pathways. ECM-optimized proteomics revealed an increased abundance of collagens II, V, and XI, along with ß-spectrin in mdxTG samples. Using ingenuity pathway analysis, we identified upstream regulators that are computationally predicted to drive compensatory changes, revealing a possible mechanism of SSPN rescue through a rewiring of cell-ECM bidirectional communication. We found that SSPN overexpression results in upregulation of key signaling molecules associated with regulation of cytoskeleton organization and mechanotransduction, including Yap1, Sox9, Rho, RAC, and Wnt. CONCLUSIONS: Our findings indicate that SSPN overexpression rescues dystrophin deficiency partially through mechanotransduction signaling cascades mediated through components of the ECM and the cortical cytoskeleton.
Assuntos
Distrofina , Distrofia Muscular de Duchenne , Camundongos , Animais , Distrofina/genética , Distrofina/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Mecanotransdução Celular , Multiômica , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Citoesqueleto/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismoRESUMO
Peak knee valgus has been shown to predict anterior cruciate ligament injury. The purpose of the current study was to compare peak rate of torque development (RTD) to peak isometric torque as a predictor of peak knee valgus during landing. Twenty-three healthy females participated. Hip abductor muscle performance was quantified using 2 types of isometric contractions: sustained and rapid. Peak isometric torque was calculated from the sustained isometric contraction. Peak RTD was calculated from the rapid isometric contraction (0-50 and 0-200 ms after force initiation). Kinematic data were collected during the deceleration phase of a double-leg drop jump task. Linear regression was used to assess the ability of hip abductor muscle performance variables to predict peak knee valgus. Increased peak RTD during the 0 to 50 milliseconds window after force initiation was found to significantly predict lower peak knee valgus (P = .011, R2 = .32). In contrast, neither peak RTD from 0 to 200 milliseconds after force initiation window (P = .45, R2 = .03) nor peak isometric torque (P = .49, R2 = .03) predicted peak knee valgus. The inability of the hip abductors to rapidly generate muscular force may be more indicative of "at-risk" movement behavior in females than measures of maximum strength.
Assuntos
Lesões do Ligamento Cruzado Anterior , Fenômenos Biomecânicos , Feminino , Humanos , Contração Isométrica , Joelho , Articulação do Joelho , TorqueRESUMO
Females have been reported to utilize a feedforward control strategy during landing in which they compensate for decreased rate of torque development (RTD) of the hip extensors through earlier pre-activation of the knee extensors. The purpose of this study was to determine the influence of a 4-week hip-focused training program on hip extensor RTD and feedforward control of the hip and knee extensors. Twenty-one females underwent hip extensor RTD evaluation and electromyographic assessment of the hip and knee extensors during a drop-jump task. Post-training, there was a significant improvement in hip extensor RTD (21.68 ± 5.44 to 23.33 ± 5.45 Nm/kg s, p = 0.009), and pre-activation of the hip extensors (87.1 ± 63.6 to 56.2 ± 60.9 ms, p < 0.001) and knee extensors (272.3 ± 113.8 to 124.0 ± 67.7 ms, p < 0.001) occurred closer to ground contact. A negative association was found between the change in hip extensor RTD and the change in knee extensor onset (r = -0.48, p = 0.03). We propose that the observed change in feedforward control is reflective of the decreased need for preparatory muscle activity owing to the improved capacity of the hip extensors to rapidly generate force.
Assuntos
Articulação do Joelho , Músculo Esquelético , Feminino , Humanos , Joelho , TorqueRESUMO
The purpose of this study was to determine whether women demonstrate decreased rate of torque development (RTD) of the hip and knee extensors and altered onset timing of the vastus lateralis and gluteus maximus during a drop-jump task when compared with men. On average, women demonstrated significantly lower normalized RTD of the hip extensors (women: 11.6 ± 1.3 MVT.s-1, men: 13.1 ± 0.9 MVT.s-1; p ≤ .01); however, there was no significant difference in knee extensor RTD. Women also demonstrated significantly earlier activation of their vastus lateralis (women: 206.0 ± 130.6 ms, men: 80.9 ± 69.6 ms; p ≤ .01) and gluteus maximus (women: 85.7 ± 58.6 ms, men: 54.5 ± 35.4 ms; p = .02). In both men and women, there was a significant negative correlation between the hip extensor RTD and the vastus lateralis electromyographic onset time (men: r = -.386, p = .046; women: r = -.531, p = .008). The study findings suggest that women may utilize a feedforward control strategy in which they activate their knee extensors earlier than men to compensate for deficits in hip extensor RTD. The impaired capacity to rapidly stabilize the hip and knee joints during dynamic maneuvers may contribute to the increased risk of anterior cruciate ligament injury observed in women.
Assuntos
Fenômenos Biomecânicos/fisiologia , Quadril/fisiologia , Joelho/fisiologia , Caracteres Sexuais , Adulto , Feminino , Humanos , Masculino , Músculo Esquelético/fisiologia , TorqueRESUMO
Age-related declines in skeletal muscle regeneration have been attributed to muscle stem cell (MuSC) dysfunction. Aged MuSCs display a fibrogenic conversion, leading to fibrosis and impaired recovery after injury. Although studies have demonstrated the influence of in vitro substrate characteristics on stem cell fate, whether and how aging of the extracellular matrix (ECM) affects stem cell behavior has not been investigated. Here, we investigated the direct effect of the aged muscle ECM on MuSC lineage specification. Quantification of ECM topology and muscle mechanical properties reveals decreased collagen tortuosity and muscle stiffening with increasing age. Age-related ECM alterations directly disrupt MuSC responses, and MuSCs seeded ex vivo onto decellularized ECM constructs derived from aged muscle display increased expression of fibrogenic markers and decreased myogenicity, compared to MuSCs seeded onto young ECM. This fibrogenic conversion is recapitulated in vitro when MuSCs are seeded directly onto matrices elaborated by aged fibroblasts. When compared to young fibroblasts, fibroblasts isolated from aged muscle display increased nuclear levels of the mechanosensors, Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ), consistent with exposure to a stiff microenvironment in vivo. Accordingly, preconditioning of young fibroblasts by seeding them onto a substrate engineered to mimic the stiffness of aged muscle increases YAP/TAZ nuclear translocation and promotes secretion of a matrix that favors MuSC fibrogenesis. The findings here suggest that an age-related increase in muscle stiffness drives YAP/TAZ-mediated pathogenic expression of matricellular proteins by fibroblasts, ultimately disrupting MuSC fate.