Age-related nitration/dysfunction of myogenic stem cell activator HGF.

Mechanical perturbation triggers activation of resident myogenic stem cells to enter the cell cycle through a cascade of events including hepatocyte growth factor (HGF) release from its extracellular tethering and the subsequent presentation to signaling-receptor c-met. Here, we show that with aging, extracellular HGF undergoes tyrosine-residue (Y) nitration and loses c-met binding, thereby disturbing muscle homeostasis. Biochemical studies demonstrated that nitration/dysfunction is specific to HGF among other major growth factors and is characterized by its locations at Y198 and Y250 in c-met-binding domains.

Preliminary Study of S100B and Sema3A Expression Patterns in Regenerating Muscle Implicates P75-Expressing Terminal Schwann Cells and Muscle Satellite Cells in Neuromuscular Junction Restoration.

Terminal Schwann cells (TSCs) help regulate the formation, maintenance, function, and repair of neuromuscular junctions (NMJs) and axon guidance after muscle injury. Premature activation of muscle satellite cells (SCs), induced by isosorbide dinitrate (ISDN) before injury, accelerates myogenic regeneration, disrupts NMJ remodeling and maturation, decreases Sema3A protein-induced neuro-repulsion, and is accompanied by time-dependent changes in S100B protein levels. Here, to study the effects of premature SC activation on TSCs and SCs, both expressing P75 nerve growth-factor receptor, hybridization was used to identify transcripts of S100B and Sema3A, and the number, intensity, and diameter of expression sites were analyzed.

A pilot study on nitration/dysfunction of NK1 segment of myogenic stem cell activator HGF.

Protein tyrosine residue (Y) nitration, a post-translational chemical-modification mode, has been associated with changes in protein activity and function; hence the accumulation of specific nitrated proteins in tissues may be used to monitor the onset and progression of pathological disorders. To verify the possible impact of nitration on postnatal muscle growth and regeneration, a pilot study was designed to examine the nitration/dysfunction of hepatocyte growth factor (HGF), a key ligand that is released from the extracellular tethering and activates myogenic stem satellite cells to enter the cell cycle upon muscle stretch and injury. Exposure of recombinant HGF (a hetero-dimer of α- and β-chains) to peroxynitrite induces Y nitration in HGF α-chain under physiological conditions.

Key concepts in muscle regeneration: muscle "cellular ecology" integrates a gestalt of cellular cross-talk, motility, and activity to remodel structure and restore function.

This review identifies some key concepts of muscle regeneration, viewed from perspectives of classical and modern research. Early insights noted the pattern and sequence of regeneration across species was similar, regardless of the type of injury, and differed from epimorphic limb regeneration. While potential benefits of exercise for tissue repair was debated, regeneration was not presumed to deliver functional restoration, especially after ischemia-reperfusion injury; muscle could develop fibrosis and ectopic bone and fat.

Lower Extremity Kinematics of the Y-Balance Test in Healthy and ACL Injured Adolescent Females.

Background: Adolescent females are at significant risk for sustaining an ACL injury. The Y-Balance Test (YBT) is frequently used to evaluate neuromuscular control and lower extremity function. However, few studies have quantified 2D lower extremity kinematics during performance of the YBT, and there is an absence of kinematic data specific to at-risk adolescent females.

Premature satellite cell activation before injury accelerates myogenesis and disrupts neuromuscular junction maturation in regenerating muscle.

Satellite cell (SC) activation, mediated by nitric oxide (NO), is essential to myogenic repair, whereas myotube function requires innervation. Semaphorin (Sema) 3A, a neuro-chemorepellent, is thought to regulate axon guidance to neuromuscular junctions (NMJs) during myotube differentiation. We tested whether "premature" SC activation (SC activation before injury) by a NO donor (isosorbide dinitrate) would disrupt early myogenesis and/or NMJs.

Traction and attraction: haptotaxis substrates collagen and fibronectin interact with chemotaxis by HGF to regulate myoblast migration in a microfluidic device.

Cell migration is central to development, wound healing, tissue regeneration, and immunity. Despite extensive knowledge of muscle regeneration, myoblast migration during regeneration is not well understood. C2C12 mouse myoblast migration and morphology were investigated using a triple-docking polydimethylsiloxane-based microfluidic device in which cells moved under gravity-driven laminar flow on uniform (=) collagen (CN=), fibronectin (FN=), or opposing gradients (CN-FN or FN-CN).

A focused review of myokines as a potential contributor to muscle hypertrophy from resistance-based exercise.

Purpose: Resistance exercise induces muscle growth and is an important treatment for age-related losses in muscle mass and strength. Myokines are hypothesized as a signal conveying physiological information to skeletal muscle, possibly to "fine-tune" other regulatory pathways. While myokines are released from skeletal muscle following contraction, their role in increasing muscle mass and strength in response to resistance exercise or training is not established.

Integration of Publicly Reported Center Outcomes into Standards and Accreditation: The FACT Model.

The rapid evolution of blood and marrow transplantation (BMT), coupled with diverse outcomes associated with heterogeneous groups of patients, led to the formation of 2 important organizations early in the development of the field: the Center for International Blood and Marrow Transplant Research (CIBMTR) and the Foundation for the Accreditation of Cellular Therapy (FACT). These organizations have addressed 2 of the 9 elements identified by the National Quality Strategy (NQS) for achieving better health care, more affordable care, and healthy people and communities: a registry that promotes improvement of care and accreditation based on quality standards. More recently, a federally mandated database in the United States addresses the third element of the NQS: public reporting of treatment results.

Stromal Content Is Correlated With Tissue Site, Contrast Retention, and Survival in Pancreatic Adenocarcinoma.

Purpose: Desmoplastic stroma is a cardinal feature of primary pancreatic ductal adenocarcinoma (PDAC), but its effects on the biology, prognosis and therapeutic outcomes are not known. We developed an automated method to assess tumor stroma density (TSD) and investigated computed tomography (CT)-correlates of stroma in PDAC.

Patients And Methods: We collected PDAC samples from rapid autopsy and resection series and digitally annotated samples to quantify TSD.

Emerging Development of Microfluidics-Based Approaches to Improve Studies of Muscle Cell Migration.

The essential interactions between and among cells in the three types of muscle tissue in development, wound healing, and regeneration of tissues, are underpinned by the ability of cardiac, smooth, and skeletal muscle cells to migrate in maintaining functional capacity after pathologies such as myocardial infarction, tissue grafting, and traumatic and postsurgical injury. Microfluidics-based devices now offer significant enhancement over conventional approaches to studying cell chemotaxis and haptotaxis that are inherent in migration. Advances in experimental approaches to muscle cell movement and tissue formation will contribute to innovations in tissue engineering for patching wound repair and muscle tissue replacement.

A mechanism for semaphorin-induced apoptosis: DNA damage of endothelial and myogenic cells in primary cultures from skeletal muscle.

One hallmark of cancer is its ability to recruit a vascular supply to support rapid growth. Suppression of angiogenesis holds potential as a second-line or adjuvant therapy to stunt cancer growth, progression, metastasis, and post-resection regeneration. To begin to test the hypothesis that semaphorin 3A and 3F together, will induce endothelial cell apoptosis by inducing DNA damage, mixed primary cultures isolated from normal adult mouse skeletal muscle were treated for 48 hr with Sema3A ± Sema3F (100ng/mL).

Pharmaceutical Characterization of MyoNovin, a Novel Skeletal Muscle Regenerator: in silico, in vitro and in vivo Studies.

Purpose: MyoNovin is a novel skeletal muscle-regenerating compound developed through synthesis of two nitro groups onto a guaifenesin backbone to deliver nitric oxide to skeletal muscle with a potential to treat muscle atrophy. The purpose of this study was to utilize in silico, in vitro, and in vivo approaches to characterize MyoNovin and examine its safety, biodistribution, and feasibility for drug delivery.

Methods: In silico software packages were used to predict the physicochemical and biopharmaceutical properties of MyoNovin.

Nitric oxide treatment attenuates muscle atrophy during hind limb suspension in mice.

Unlabelled: Debilitating muscle-disuse atrophy in aging or obesity has huge socioeconomic impact. Since nitric oxide (NO) mediates muscle satellite cell activation and induces hypertrophy with exercise in old mice, we tested whether treatment with the NO donor, isosorbide dinitrate (ISDN), during hind limb suspension would reduce atrophy. Mice were suspended 18 days, with or without daily ISDN (66mg/kg).

Slow-Myofiber Commitment by Semaphorin 3A Secreted from Myogenic Stem Cells.

Recently, we found that resident myogenic stem satellite cells upregulate a multi-functional secreted protein, semaphorin 3A (Sema3A), exclusively at the early-differentiation phase in response to muscle injury; however, its physiological significance is still unknown. Here we show that Sema3A impacts slow-twitch fiber generation through a signaling pathway, cell-membrane receptor (neuropilin2-plexinA3) → myogenin-myocyte enhancer factor 2D → slow myosin heavy chain. This novel axis was found by small interfering RNA-transfection experiments in myoblast cultures, which also revealed an additional element that Sema3A-neuropilin1/plexinA1, A2 may enhance slow-fiber formation by activating signals that inhibit fast-myosin expression.

Altered Satellite Cell Responsiveness and Denervation Implicated in Progression of Rotator-Cuff Injury.

Background: Rotator-cuff injury (RCI) is common and painful; even after surgery, joint stability and function may not recover. Relative contributions to atrophy from disuse, fibrosis, denervation, and satellite-cell responsiveness to activating stimuli are not known.

Methods And Findings: Potential contributions of denervation and disrupted satellite cell responses to growth signals were examined in supraspinatus (SS) and control (ipsilateral deltoid) muscles biopsied from participants with RCI (N = 27).

Fibrosis, low vascularity, and fewer slow fibers after rotator-cuff injury.

Introduction: Rotator-cuff injury (RCI) represents 50% of shoulder injuries, and prevalence increases with age. Even with successful tendon repair, muscle and joint function may not return.

Methods: To explore the dysfunction, supraspinatus and ipsilateral deltoid (control) muscles were biopsied during arthroscopic RCI repair for pair-wise histological and protein-expression studies.

Fast-to-slow shift of muscle fiber-type composition by dietary apple polyphenols in rats: Impact of the low-dose supplementation.

Our previous studies demonstrated that an 8-week intake of 5% (w/w) apple polyphenol (APP) in the diet improves muscle endurance of young-adult rats. In order to identify a lower limit of the dietary contribution of APP to the effect, the experiments were designed for lower-dose supplementation (8-week feeding of 0.5% APP in AIN-93G diet) to 12-week-old male Sprague-Dawley rats.

The role of semaphorin3A in myogenic regeneration and the formation of functional neuromuscular junctions on new fibres.

Current research on skeletal muscle injury and regeneration highlights the crucial role of nerve-muscle interaction in the restoration of innervation during that process. Activities of muscle satellite or stem cells, recognized as the 'currency' of myogenic repair, have a pivotal role in these events, as shown by ongoing research. More recent investigation of myogenic signalling events reveals intriguing roles for semaphorin3A (Sema3A), secreted by activated satellite cells, in the muscle environment during development and regeneration.

Hepatocyte Growth Factor and Satellite Cell Activation.

Satellite cells are the "currency" for the muscle growth that is critical to meat production in many species, as well as to phenotypic distinctions in development at the level of species or taxa, and for human muscle growth, function and regeneration. Careful research on the activation and behaviour of satellite cells, the stem cells in skeletal muscle, including cross-species comparisons, has potential to reveal the mechanisms underlying pathological conditions in animals and humans, and to anticipate implications of development, evolution and environmental change on muscle function and animal performance.

Transmembrane proteoglycans syndecan-2, 4, receptor candidates for the impact of HGF and FGF2 on semaphorin 3A expression in early-differentiated myoblasts.

Regenerative mechanisms that regulate intramuscular motor innervation are thought to reside in the spatiotemporal expression of axon-guidance molecules. Our previous studies proposed an unexplored role of resident myogenic stem cell (satellite cell)-derived myoblasts as a key presenter of a secreted neural chemorepellent semaphorin 3A (Sema3A); hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGF2) triggered its expression exclusively at the early differentiation phase. In order to advance this concept, the present study described that transmembrane heparan/chondroitin sulfate proteoglycans syndecan-2, 4 may be the plausible receptor candidates for HGF and FGF2 to signal Sema3A expression.

Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival rate of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, including data from primary tumor, metastatic and normal samples.

Diet-induced obesity impairs muscle satellite cell activation and muscle repair through alterations in hepatocyte growth factor signaling.

A healthy skeletal muscle mass is essential in attenuating the complications of obesity. Importantly, healthy muscle function is maintained through adequate repair following overuse and injury. The purpose of this study was to investigate the impact of diet-induced obesity (DIO) on skeletal muscle repair and the functionality of the muscle satellite cell (SC) population.