Everything you always wanted to know about SYNEMIN and never dared to ask

Synemin, a type IV intermediate filament (IF) protein, forms a bridge between IFs and cellular membrane, by interacting with Desmin, Vinculin, Talin and Dystrophin. An A-kinase anchoring protein, it also provides temporal and spatial targeting of protein kinase A. This protein likely functions to integrate mechanical stress and maintain structural integrity and tissue homeostasis in skeletal muscle and other cells.

In our recent article, entitled "Synemin acts as a regulator of signalling molecules during skeletal muscle hypertrophy" (Li et al. J Cell Sci, 2014) we provide novel evidence on its role by phenotyping the synemin null mice. All the additional hints and informations on synemin role in development and postnatal life in PubMed.

Inflammation in Muscle Repair, Aging, and Myopathies

I have recently had the honor to co-edit a special issue of BioMed Research International dedicated to the role of inflammation in various acute and chronic conditions of muscle loss and disease. Our group in Rome participated to the special issue with a paper (from which the figure is extracted) confirming in vivo a role for the neurohypophyseal hormone vasopressin in muscle repair and homeostasis. The paper by Alessandra Costa et al., entitled "Local Overexpression of V1a-Vasopressin Receptor Enhances Regeneration in Tumor Necrosis Factor-Induced Muscle Atrophy" can be found by fillowing the link.

Figure legend. V1aR overexpression counteracts TNF-dependent protein degradation by stimulating the Akt pathway. (a) Western blots of phosphorylated Akt and native and phosphorylated FoxO3a expression demonstrate that in muscle overexpressing TNF, phospho-Akt and phospho-FoxO3a are downregulated, while the native Foxo3a is increased. In V1aR overexpressing muscles, the expression levels of phospho-FoxO3a and phospho-Akt is increased compared with TNF alone, while the native Foxo3a is reduced. (b–d) Densitometric analysis of three independent experiments of phospho-Akt, phospho-FoxO3a, and native FoxO3a expression levels. (e) Real-time PCR analysis revealed that the strong upregulation of atrogin-1 expression observed in the sample overexpressing TNF alone is downregulated in V1aR+TNF-transfected muscles. ; by Student’s -test.

Here is the Table of content of the special issue, a nice mix of original research and review articles. Inflammation in Muscle Repair, Aging, and Myopathies Guest Editors: Marina Bouché, Pura Muñoz-Cánoves, Fabio Rossi, and Dario Coletti Inflammation in Muscle Repair, Aging, and Myopathies, Marina Bouché, Pura Muñoz-Cánoves, Fabio Rossi, and Dario Coletti Volume 2014 (2014), Article ID 821950, 3 pages Stem Cell Transplantation for Muscular Dystrophy: The Challenge of Immune Response, Sara Martina Maffioletti, Maddalena Noviello, Karen English, and Francesco Saverio Tedesco Volume 2014 (2014), Article ID 964010, 12 pages From Innate to Adaptive Immune Response in Muscular Dystrophies and Skeletal Muscle Regeneration: The Role of Lymphocytes, Luca Madaro and Marina Bouché Volume 2014 (2014), Article ID 438675, 12 pages Cardioprotective Effects of Osteopontin-1 during Development of Murine Ischemic Cardiomyopathy, Georg D. Duerr, Bettina Mesenholl, Jan C. Heinemann, Martin Zoerlein, Peter Huebener, Prisca Schneider, Andreas Feisst, Alexander Ghanem, Klaus Tiemann, Daniela Dewald, Armin Welz, and Oliver Dewald Volume 2014 (2014), Article ID 124063, 15 pages IL-6 Impairs Myogenic Differentiation by Downmodulation of p90RSK/eEF2 and mTOR/p70S6K Axes, without Affecting AKT Activity, Michele Pelosi, Manuela De Rossi, Laura Barberi, and Antonio Musarò Volume 2014 (2014), Article ID 206026, 12 pages Local Overexpression of V1a-Vasopressin Receptor Enhances Regeneration in Tumor Necrosis Factor-Induced Muscle Atrophy, Alessandra Costa, Angelica Toschi, Ivana Murfuni, Laura Pelosi, Gigliola Sica, Sergio Adamo, and Bianca Maria Scicchitano Volume 2014 (2014), Article ID 235426, 14 pages Influence of Immune Responses in Gene/Stem Cell Therapies for Muscular Dystrophies, Andrea Farini, Clementina Sitzia, Silvia Erratico, Mirella Meregalli, and Yvan Torrente Volume 2014 (2014), Article ID 818107, 16 pages Vitamin D Receptor Agonists: Suitable Candidates as Novel Therapeutic Options in Autoimmune Inflammatory Myopathy, Clara Crescioli Volume 2014 (2014), Article ID 949730, 10 pages 7-Tesla Magnetic Resonance Imaging Precisely and Noninvasively Reflects Inflammation and Remodeling of the Skeletal Muscle in a Mouse Model of Antisynthetase Syndrome, Clara Sciorati, Antonio Esposito, Lara Campana, Tamara Canu, Antonella Monno, Anna Palmisano, Francesco De Cobelli, Alessandro Del Maschio, Dana P. Ascheman, Angelo A. Manfredi, and Patrizia Rovere-Querini Volume 2014 (2014), Article ID 879703, 8 pages Understanding the Process of Fibrosis in Duchenne Muscular Dystrophy, Yacine Kharraz, Joana Guerra, Patrizia Pessina, Antonio L. Serrano, and Pura Muñoz-Cánoves Volume 2014 (2014), Article ID 965631, 11 pages Inflammation Based Regulation of Cancer Cachexia, Jill K. Onesti and Denis C. Guttridge Volume 2014 (2014), Article ID 168407, 7 pages Macrophage Plasticity in Skeletal Muscle Repair, Elena Rigamonti, Paola Zordan, Clara Sciorati, Patrizia Rovere-Querini, and Silvia Brunelli Volume 2014 (2014), Article ID 560629, 9 pages

Our editorial "Inflammation in Muscle Repair, Aging, and Myopathies" briefly summarizes the main focus of this special issue, i.e. bringing together studies that used different experimental approaches in vivo or in vitro to dissect the dynamic changes taking place in specific immune cell populations, their cross talk with other cell types within the muscle milieu, and their contribution to normal versus pathological muscle repair. While the number of scientific publications on the topic of skeletal muscle inflammation has steadily grown over the last two decades, the notion of inflammation as a common feature in muscle degeneration occurring in aging and myopathies and its association with altered muscle has to our knowledge never previously been addressed and discussed in dedicated journal issues before.

Restoration versus reconstruction: how cell anatomy and extra‐cellular matrix affect tissue regeneration

Sadly, in Italy we have a significant experience of repair following heart quakes. Two main strategies are possible and have been alternatively chosen along the decades, as shown below. Similarly, tissues respond to damage by either restoring their structure or reconstructing it ex novo, depending on the extend of the lesions as well as on the tissue type.

Here is the lecture given to the 2013 Congress of the Italian Society of Anatomy and Hsitology, entitled "Restoration versus reconstruction: how cell anatomy and extra‐cellular matrix affect tissue regeneration". Abstract published in Italian Journal of Anatomy and Embryology http://dx.doi.org/10.13128/IJAE-13961 Tissue regeneration replaces damaged cells and is involved in tissue remodeling. In order to investigate the existence of a leitmotif of tissue regeneration, we compared the cellular aspects of regeneration of epidermis, neurons and skeletal muscle, characterized by different types of histological and functional organization. Following damage, all the tissues here analyzed go through three phases: inflammation, regeneration and maturation. Another common feature is the occurrence of cellular de-differentiation and/or differentiation events, including gene transcription, which are typical of embryonic development. Nonetheless, various strategies are used by different tissues to replace their lost parts. The epidermis regenerates ex novo, whereas neurons restore their missing parts; muscle fibers use a mixed strategy, based on the regrowth of missing parts through reconstruction by means of newborn fibers. The choice of either strategy is influenced by the physical, chemical and structural features of the cells as well as by the extracellular matrix typical of a given tissue, which points to the existence of differential, evolutionary-based mechanisms for specific tissue regeneration. Taking skeletal muscle as a model, we present evidence about the importance of the fiber niche to direct and favour tissue regeneration, a phenomenon of particular relevance for highly hierarchized tissues such as striated muscles. Niche properties are accounted for by cell-cell contacts, cell-matrix interaction and paracrine effects in skeletal muscle. The ordered sequence of steps that characterizes the regeneration processes, shared by several tissues, suggests it may be possible to model this extremely important phenomenon to improve guided in situ regeneration interventions.

ARTCILES: Coletti et al. Regenerative Medicine Research 2103

Figure legend. Examples of focal injuries. (LEFT) Hematoxilin-and eosin-stained murine skeletal muscle, longitudinally sectioned to show the gaps in three adjacent fibers. The injury likely occurred following an intense exercise session (wheel running). Upon leakage of the broken sarcolemma, factors such as Wnt are released before a fast repair process known as patch repair occurs. In turn, Wnt factors trigger the activation of satellite cells and other resident interstitial cells with myogenic potential, which proliferate, migrate and fuse into small myotubes that ultimately fuse with the damaged fibers. (RIGHT) Toluidine blue-stained semithin section of a murine carotid showing damage, likely due to smooth muscle cell-restricted inactivation of the serum response factor gene. A rupture of the endothelial layer, as well as of the elastin matrix, with exposure of underlying cells is visible; release of intracellular factors (von Willebrand Factor) and exposure of undisclosed antigens (collagen) are essential for the subsequent phases of clot formation, remodeling and repair of the wall defect. Bar = 25 micron.

Figure legend. Macrophages infiltrate necrotic muscle fibers. Serial section of murine skeletal muscle in an area of necrosis; corresponding fibers are highlighted by matching color arrows. Evans Blue Dye (EBD) highlights muscle fibers whose plasma membrane is leaking owing to damage; hematoxylin and eosin staining (H&E), showing cellular infiltration in EBD + fibers; histochemistry for esterase staining highlights esterase-enriched macrophages; immunofluorescence analysis for activated macrophages expressing F4/80 (green) confirms the invasion of the muscle fibers by macropohages: laminin (red) and nuclei (blue) are also shown. Coletti et al. Regenerative Medicine Research 2013 1:4 doi:10.1186/2050-490X-1-4

In this review article we present and compare the cellular aspects of regeneration in skin, nerve and muscle, three organs characterized by differences not only in anatomical and functional organization, but also in the number and location of stem cell niches and populations, which ultimately result in varying regenerative potential. By discussing the common traits and the specific features of regeneration in three model tissues, we propose general models of regeneration and highlight various strategies adopted to cope with damage and repair in mammals.The strategies used by a wide range of tissues to replace their lost parts vary, probably as result of evolutionary-based mechanisms for specific tissue regeneration. While the epidermis regenerates ex novo, neurons restore their missing parts; muscle fibers instead use a mixed strategy, based on the reconstruction of missing parts and on the generation of new fibers. These differential strategies are represented by the two terms used in the title to refer to different forms of regeneration: restoration, the attempt to re-establish the status quo ante, and reconstruction, a more radical response, characterized by ex novo cell colonization and tissue formation. The choice of either strategy is deeply influenced by the anatomy and the distribution/features of stem cell niches typical of a given organ. In addition, the energetic costs for either regenerative strategy are also likely to play an important role. The abstraction of divergences and analogies between different types of tissue regeneration might pave the way for the mathematical modeling of this process, thereby making a major contribution to both pathology and regenerative medicine. When talking of wound healing, a distinction is made by some authors between regeneration and repair. Regeneration is used to refer to the complete replacement of damaged tissue with new tissue not associated with scar tissue, while repair is used to refer to the re-establishment of tissue continuity [1]. Regeneration can be attained by two means: a) restoration, defined as “putting together what is broken”; b) reconstruction, defined as “replacing and rebuilding what is torn down” (according to the Merriam-Webster Dictionary). To grant homeostasis, most tissues undergo continuous or cyclic processes of regeneration. Which of the afore-mentioned strategies tissues adopt depends on the histological features discussed in the article entitled "Restoration versus reconstruction: cellular mechanisms of skin, nerve and muscle regeneration compared".

ARTICLES: He et al. Journal of Clinical investigation 2013

Cachexia is a debilitating condition characterized by extreme skeletal muscle wasting that contributes significantly to morbidity and mortality. Efforts to elucidate the underlying mechanisms of muscle loss have predominantly focused on events intrinsic to the myofiber. In contrast, less regard has been given to potential contributory factors outside the fiber within the muscle microenvironment. In tumor-bearing mice and patients with pancreatic cancer, we found that cachexia was associated with a type of muscle damage resulting in activation of both satellite and nonsatellite muscle progenitor cells. In our paper we present extensive data demonstrating that skeletal muscle wasting in cachexia arises from the failure of myogenic progenitor cells to differentiate and fuse into skeletal muscle myofibers. The failure of myogenic progenitor cells to differentiate is due to elevated, NF-kappaB dependent expression of Pax7 leading to expansion of muscle progenitors that are prevented from differentiation and fusion to repair damaged fibers. Our findings challenge the assumption that cachexia arises from events occurring inside the muscle fibers (i.e. essentially proteasome-mediated protein degradation) leading to muscle atrophy. On the contrary, the microenvironment surrounding muscle fiber and including muscle stem cell niche is important for muscle homeostasis and can be targeted to counteract muscle wasting. The link to full text article is provided here. In addition, extensive supplemental data are available here. We are currently investigating the role of Serum Response Factor (SRF) and mechanotransduction in this stem cell mediated response. A posted position to work on this topic is currently available (see related post). Figure modified from: He et al. J Clin Invest doi:10.1172/JCI68523

ARTICLES: Galmiche et al. Circulation research 2103

Common carotid intima-media thickness and distensibility are markers of structural and functional vessel wall properties, with important consequences on cardiovascular risk. We investigated whether SRF and its target genes regulate intrinsic smooth muscle tone and, in turn, arterial stiffness, and we found that inactivating SRF in vascular smooth muscle cells (VSMC) results in profound alterations of the extra-cellular matrix composition and arterial wall properties. The link to the full text article is here.

POSTDOC POSITION IN SKELETAL MUSCLE PHYSIO-PATHOLOGY AVAILABLE IMMEDIATELY

A new postdoc position is available in the lab to work on mechanotransduction and SRF role in exercise-mediated responses in cancer cachexia. The position at the University of Paris 6 Pierre et Marie Curie is for 1 year, renewable. Full detail on the position (immediately available) are visible in the attached flyer. Please send a cover letter, CV and names and email address of two references to dario.coletti@upmc.fr