Met-activating genetically improved chimeric factor-1 promotes angiogenesis and hypertrophy in adult myogenesis

BACKGROUND: Myogenic progenitor cells (activated satellite cells) are able to express both HGF and its receptor cMet. After muscle injury, HGF-Met stimulation promotes activation and primary division of satellite cells. MAGIC-F1 (Met-Activating Genetically Improved Chimeric Factor-1) is an engineered protein that contains two human Met-binding domains that promotes muscle hypertrophy. MAGIC-F1 protects myogenic precursors against apoptosis and increases their fusion ability enhancing muscle differentiation. Hemizygous and homozygous Magic-F1 transgenic mice displayed constitutive muscle hypertrophy. METHODS: Here we describe microarray analysis on Magic-F1 myogenic progenitor cells showing an altered gene signatures on muscular hypertrophy and angiogenesis compared to wild-type cells. In addition, we performed a functional analysis on Magic-F1+/+ transgenic mice versus controls using treadmill test. RESULTS: We demonstrated that Magic-F1+/+ mice display an increase in muscle mass and cross-sectional area leading to an improvement in running performance. Moreover, the presence of MAGIC-F1 affected positively the vascular network, increasing the vessel number in fast twitch fibers. Finally, the gene expression profile analysis of Magic-F1+/+ satellite cells evidenced transcriptomic changes in genes involved in the control of muscle growth, development and vascularisation. CONCLUSION: We showed that MAGIC -F1-induced muscle hypertrophy affects positively vascular network, increasing vessel number in fast twitch fibers. This was due to unique features of mammalian skeletal muscle and its remarkable ability to adapt promptly to different physiological demands by modulating the gene expression profile in myogenic progenitors

Ultrasound stimulus to enhance the bone regeneration capability of gelatin cryogels

In the present study, gelatin-based cryogels have been seeded with human SAOS-2 osteoblasts. In order to overcome the drawbacks associated with in vitro culture systems, such as limited diffusion and inhomogeneous cell-matrix distribution, this work describes the application of ultrasounds (average power, 149 mW; frequency, 1.5 MHz) to physically enhance the cell culture in vitro. The results indicate that the physical stimulation of cell-seeded gelatin-based cryogels upregulates the bone matrix production

Mesoangioblasts at 20: from the embryonic aorta to the patient bed

In 2002 we published an article describing a population of vessel-associated progenitors that we termed mesoangioblasts (MABs). During the past decade evidence had accumulated that during muscle development and regeneration things may be more complex than a simple sequence of binary choices (e.g., dorsal vs. ventral somite). LacZ expressing fibroblasts could fuse with unlabelled myoblasts but not among themselves or with other cell types. Bone marrow derived, circulating progenitors were able to participate in muscle regeneration, though in very small percentage. Searching for the embryonic origin of these progenitors, we identified them as originating at least in part from the embryonic aorta and, at later stages, from the microvasculature of skeletal muscle. While continuing to investigate origin and fate of MABs, the fact that they could be expanded in vitro (also from human muscle) and cross the vessel wall, suggested a protocol for the cell therapy of muscular dystrophies. We tested this protocol in mice and dogs before proceeding to the first clinical trial on Duchenne Muscular Dystrophy patients that showed safety but minimal efficacy. In the last years, we have worked to overcome the problem of low engraftment and tried to understand their role as auxiliary myogenic progenitors during development and regeneration

Magic-factor 1, a partial agonist of Met, induces muscle hypertrophy by protecting myogenic progenitors from apoptosis.

Hepatocyte Growth Factor (HGF) is a pleiotropic cytokine of mesenchymal origin that mediates a characteristic array of biological activities including cell proliferation, survival, motility and morphogenesis. Its high affinity receptor, the tyrosine kinase Met, is expressed by a wide range of tissues and can be activated by either paracrine or autocrine stimulation. Adult myogenic precursor cells, the so called satellite cells, express both HGF and Met. Following muscle injury, autocrine HGF-Met stimulation plays a key role in promoting activation and early division of satellite cells, but is shut off in a second phase to allow myogenic differentiation. In culture, HGF stimulation promotes proliferation of muscle precursors thereby inhibiting their differentiation

The florentine anatomical wax models in the collection of Antonio Scarpa

In 1804, the famous surgeon and anatomist Antonio Scarpa (1752-1832) listed a collection of 350 natural preparations in the catalogue of his Anatomical Museum at the University of Pavia, Index Rerum Musei Anatomici Ticinensi

Cardiac development and remodelling in Magic-F1 transgenic mice

MAGIC-F1 (Met Activating Genetically Improved Chimeric Factor 1) is a human recombi- nant protein, derived from dimerization of the receptor-binding domain of hepatocyte growth factor (HGF). Previous experiments demonstrated that skeletal muscle specific expression of Magic-F1 can induce constitutive muscular hypertrophy, improve running performance and accelerate muscle regeneration after injury in hemizigous transgenic mice [1]. Furthermore, the microarray analysis of Magic-F1+/+ satellite cells showed transcriptomic changes in genes involved in the control of muscle growth, development and vascularisation [2]. In this study we demonstrate that Magic-F1 mice show an alteration of the heart morphol- ogy. Morphometric analysis and three-dimensional reconstruction of the hearth revealed that MAGIC-F1 paracrine effect is able to induce a robust remodelling of the left ventricle cham- ber in transgenic mice. Interestingly, we found in Magic-F1 hearts an alteration of Phd2 and HIF1 protein levels. These two oxygen sensors are found dysregulated in cardiac ischaemic conditions, where generalised hypoxia causes functional impairments in cardiomyocytes and structural tissue damage [3-4]. These preliminary results support the involvement of oxygen sensors in Magic-F1-induced cardiac hypertrophy and dilation. In addition, Magic-F1+/+ mice can be used as non-pressure overload model to further investigate the role of oxygen-sensors in ischaemic heart disease. To better understand the biological effects of MAGIC-F1 on the mor- phology and function of cardiac muscle, more detailed studies are required. It could be also interesting to have a longer follow-up of the homozygous animals, to investigate the progres- sion of the cardiac remodelling upon a double dose of MAGIC-F1

BMI and inverted BMI as predictors of fat mass in young people: a comparison across the ages

Background: The use of body mass index (BMI) could lead to over/under estimation of fat mass percentage (FM%). An alternative index (inverted BMI, iBMI) has been proposed as a better estimator of FM% in adults, while its practical feasibility in children and adolescents has not been fully investigated. Aim: To examine if iBMI can better estimate FM% than BMI in children/adolescents. Subjects and methods: Height, weight, and triceps and subscapularis skinfolds were measured in 6686 schoolchildren aged 11-14-years-old. BMI and iBMI (squared height/weight) were calculated; FM% was estimated by skinfold thicknesses. The Pearson correlation coefficient and the coefficient of determination were obtained to test the best regression model between the indexes and FM%. Results: FM% was linearly related to both indexes with R2 values that were overall > 0.7. No significant differences among the R2 values were found (p value = .2, ANOVA). Conclusion: BMI persists as a robust index for health surveillance screening in children/adolescents, being very intuitive and ready-to-use. Inverted BMI may be more accurate within a cohort of adults who experience only ponderal modifications, directly implicated in the variation of FM. In conclusion, the BMI remains a quick, handy and intuitive predictor of FM%