Muscle expression of a local Igf-1 isoform protects motor neurons in an ALS mouse model

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a selective degeneration of motor neurons, atrophy, and paralysis of skeletal muscle. Although a significant proportion of familial ALS results from a toxic gain of function associated with dominant SOD1 mutations, the etiology of the disease and its specific cellular origins have remained difficult to define. Here, we show that muscle-restricted expression of a localized insulin-like growth factor (Igf) -1 isoform maintained muscle integrity and enhanced satellite cell activity in SOD1G93A transgenic mice, inducing calcineurin-mediated regenerative pathways. Muscle-specific expression of local Igf-1 (mIgf-1) isoform also stabilized neuromuscular junctions, reduced inflammation in the spinal cord, and enhanced motor neuronal survival in SOD1G93A mice, delaying the onset and progression of the disease. These studies establish skeletal muscle as a primary target for the dominant action of inherited SOD1 mutation and suggest that muscle fibers provide appropriate factors, such as mIgf-1, for neuron survival

Skeletal muscle myopenia in mice model of bile duct ligation and carbon tetrachloride-induced liver cirrhosis

Skeletal muscle myopathy is universal in cirrhotic patients, however, little is known about the main mechanisms involved. The study aims to investigate skeletal muscle morphological, histological, and functional modifications in experimental models of cirrhosis and the principal molecular pathways responsible for skeletal muscle myopathy. Cirrhosis was induced by bile duct ligation (BDL) and carbon tetrachloride (CCl4) administration in mice. Control animals (CTR) underwent bile duct exposure or vehicle administration only. At sacrifice, peripheral muscles were dissected and weighed. Contractile properties of extensor digitorum longus (EDL) were studied in vitro. Muscle samples were used for histological and molecular analysis. Quadriceps muscle histology revealed a significant reduction in cross-sectional area of muscle and muscle fibers in cirrhotic mice with respect to CTR. Kinetic properties of EDL in both BDL and CCl4 were reduced with respect to CTR; BDL mice also showed a reduction in muscle force and a decrease in the resistance to fatigue. Increase in myostatin expression associated with a decrease in AKT-mTOR expressions was observed in BDL mice, together with an increase in LC3 protein levels. Upregulation of the proinflammatory citochines TNF-a and IL6 and an increased expression of NF-kB and MuRF-1 were observed in CCl4 mice. In conclusion, skeletal muscle myopenia was present in experimental models of BDL and CCl4-induced cirrhosis. Moreover, reduction in protein synthesis and activation of protein degradation were the main mechanisms responsible for myopenia in BDL mice, while activation of ubiquitin-pathway through inflammatory cytokines seems to be the main potential mechanism involved in CCl4 mice

EFFECT OF CONSERVATION PRACTICES ON FUNCTIONAL DIVERSITY AND ASSEMBLY OF WEED COMMUNITIES: A DATABASE OF FUNCTIONAL TRAITS

The incorporation of conservation agriculture techniques (e.g. reduced tillage and green manures) in organic farming systems brings many benefits to the environment and reduces energy use (Holland, 2004). One of the main drawbacks of the use of reduced tillage is the potential increase in weed infestation and shifts in the weed community composition, sometimes to the benefit of more difficult-to-control species (Bàrberi, 2002; Peigné et al., 2007; Sans et al., 2011). However, weeds have an important role in maintaining farmland functional biodiversity (Bàrberi et al, 2010; Caballero et al., 2010), and this should be balanced with their potential negative impact on crop yield and quality. Within the frame of the European project “Reduced tillage and green manures for sustainable cropping systems” (TILMAN-ORG), in 2012 we started a study with the aim of evaluating the effects of conservation agricultural methods on functional attributes of weed communities, taking into account both the potential detrimental effects of weeds on crop growth and yield and the potential ecological services or dis-services. Knowledge on the outcome of positive and negative effects will be useful in the context of evaluating soil conservation practices in organic farming. In this paper we highlight the approach used to build the weed functional traits database, the first step in this study

Seismic location improvements from an OBS/H temporary network in Southern Tyrrhenian Sea

We present the first investigation performed on the seismicity of Southern Tyrrhenian Sea, off-shore Sicily with the contribution of data from broad-band ocean bottom seismometers and hydrophones (OBS/H). Offshore data were recorded during the TYrrhenian Deep sea Experiment (TYDE) from December 2000 to May 2001 in the Southern Tyrrhenian Sea. Hypocenter locations of a cluster of 53 seismic events occurred in March 2001 in north-eastern Sicily were estimated by the integration of land (permanent network) and offshore (temporary network) data and compared with locations estimated from land data only. The scatter of the cluster was evaluated by dispersion parameters. The off-shore data significantly reduced the scatter of the swarm hypocenters also restricting the depth range of the cluster. Moreover, space trends of the event distribution originally shown by the land data were only partially confirmed by the land-sea joint data. In order to assess the efficiency in terms of hypocenter mislocations in the subject area, of a land-sea integrated network with respect to a land-based network, we performed simulations by assuming a grid distribution of earthquakes and a recent local 3D velocity model, computing synthetic arrival times of body waves to the stations of both network configurations (integrated and land-based) perturbing the computed times and relocating earthquakes by inversion. The results of the synthetic tests demonstrated that the presence of sea bottom stations in the Tyrrhenian basin can reduce the mislocations of large magnitude and/or superficial earthquakes in the southernmost Calabria and Messina Strait and of low magnitude and/or deep earthquakes in north-eastern Sicily. The major accuracy of synthetic earthquake locations obtained including OBS/H data provides an additional support to the interpretation of the cluster occurred in March 2001 and to the opportunity of long-term installation of an off-shore network like TYDE in the study region

Effects of IGF-1 isoforms on muscle growth and sarcopenia.

The decline in skeletal muscle mass and strength occurring in aging, referred as sarcopenia, is the result of many factors including an imbalance between protein synthesis and degradation, changes in metabolic/hormonal status, and in circulating levels of inflammatory mediators. Thus, factors that increase muscle mass and promote anabolic pathways might be of therapeutic benefit to counteract sarcopenia. Among these, the insulin-like growth factor-1 (IGF-1) has been implicated in many anabolic pathways in skeletal muscle. IGF-1 exists in different isoforms that might exert different role in skeletal muscle. Here we study the effects of two full propeptides IGF-1Ea and IGF-1Eb in skeletal muscle, with the aim to define whether and through which mechanisms their overexpression impacts muscle aging. We report that only IGF-1Ea expression promotes a pronounced hypertrophic phenotype in young mice, which is maintained in aged mice. Nevertheless, examination of aged transgenic mice revealed that the local expression of either IGF-1Ea or IGF-1Eb transgenes was protective against age-related loss of muscle mass and force. At molecular level, both isoforms activate the autophagy/lysosome system, normally altered during aging, and increase PGC1-α expression, modulating mitochondrial function, ROS detoxification, and the basal inflammatory state occurring at old age. Moreover, morphological integrity of neuromuscular junctions was maintained and preserved in both MLC/IGF-1Ea and MLC/IGF-1Eb mice during aging. These data suggest that IGF-1 is a promising therapeutic agent in staving off advancing muscle weakness

Metabolic changes associated with muscle expression of SOD1G93A

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder, classified into sporadic or familial forms and characterized by motor neurons death, muscle atrophy, weakness, and paralysis. Among the familial cases of ALS, approximately 20% are caused by dominant mutations in the gene coding for superoxide dismutase (SOD1) protein. Of note, mutant SOD1 toxicity is not necessarily limited to the central nervous system. ALS is indeed a multi-systemic and multifactorial disease that affects whole body physiology and induces severe metabolic changes in several tissues, including skeletal muscle. Nevertheless, whether alterations in the plasticity, heterogeneity, and metabolism of muscle fibers are the result of motor neuron degeneration or alternatively occur independently of it remain to be elucidated. To address this issue, we made use of a mouse model (MLC/SOD1G93A) that overexpresses the SOD1 mutant gene selectively in skeletal muscle. We found an alteration in the metabolic properties of skeletal muscle characterized by alteration in fiber type composition and metabolism. Indeed, we observed an alteration of muscle glucose metabolism associated with the induction of Phosphofructokinases and Pyruvate dehydrogenase kinase 4 expression. The upregulation of Pyruvate dehydrogenase kinase 4 led to the inhibition of Pyruvate conversion into Acetyl-CoA. Moreover, we demonstrated that the MLC/SOD1G93Atransgene was associated with an increase of lipid catabolism and with the inhibition of fat deposition inside muscle fibers. All together these data demonstrate that muscle expression of the SOD1G93Agene induces metabolic changes, along with a preferential use of lipid energy fuel by muscle fibers. We provided evidences that muscle metabolic alterations occurred before disease symptoms and independently of motor neuron degeneration, indicating that skeletal muscle is likely an important therapeutic target in ALS

Electrical stimulation counteracts muscle atrophy associated with aging in humans

Functional and structural muscle decline is a major problem during aging. Our goal was to improve in old subjects quadriceps m. force and mobility functional performances (stair test, chair rise test, timed up and go test) with neuromuscular electrical stimulation (9 weeks, 2-3times/week, 20-30 minutes per session). Furthermore we performed histological and biological molecular analyses of vastus lateralis m. biopsies. Our findings demonstrate that electrical stimulation significantly improved mobility functional performancies and muscle histological characteristics and molecular markers

Effects of IGF\u20101 isoforms on muscle growth and sarcopenia

The decline in skeletal muscle mass and strength occurring in aging, referred as sar\u2010copenia, is the result of many factors including an imbalance between protein synthe\u2010sis and degradation, changes in metabolic/hormonal status, and in circulating levels of inflammatory mediators. Thus, factors that increase muscle mass and promote anabolic pathways might be of therapeutic benefit to counteract sarcopenia. Among these, the insulin\u2010like growth factor\u20101 (IGF\u20101) has been implicated in many anabolic pathways in skeletal muscle. IGF\u20101 exists in different isoforms that might exert differ\u2010ent role in skeletal muscle. Here we study the effects of two full propeptides IGF\u20101Ea and IGF\u20101Eb in skeletal muscle, with the aim to define whether and through which mechanisms their overexpression impacts muscle aging. We report that only IGF\u20101Ea expression promotes a pronounced hypertrophic phenotype in young mice, which is maintained in aged mice. Nevertheless, examination of aged transgenic mice revealed that the local expression of either IGF\u20101Ea or IGF\u20101Eb transgenes was protective against age\u2010related loss of muscle mass and force. At molecular level, both isoforms activate the autophagy/lysosome system, normally altered during aging, and increase P GC1\u2010\u3b1 expression, modulating mitochondrial function, ROS detoxification, and the basal inflammatory state occurring at old age. Moreover, morphological integrity of neuromuscular junctions was maintained and preserved in both MLC/IGF\u20101Ea and MLC/IGF\u20101Eb mice during aging. These data suggest that IGF\u20101 is a promising thera\u2010peutic agent in staving off advancing muscle weakness

Designing and implementing a multi-scalar approach to Maritime Spatial Planning: The case study of Italy

The Italian coastal and marine space includes areas with remarkable differences in terms of oceanographic characteristics, maritime uses, natural habitats, species distribution, landscape and cultural heritage. In Italy, coastal and marine management competencies are shared among national, regional, and for some aspects even local authorities. This geographic heterogeneity and governance complexity required the adoption of a multiscalar approach to Maritime Spatial Planning (MSP). Such an approach aims at implementing decision-making and spatial planning at multiple and nested scales. In the case of Italy, the multi-scalar approach included the definition of national guidelines and the development of three maritime spatial (MS) plans, one for each maritime area (Adriatic, Ionian and Central Mediterranean, and Tyrrhenian and Western Mediterranean), including subareas and nested planning units. The development of the MS plans involved competent Ministries, the coastal Regions and several researchers. Based on the description of the adopted six-phase methodology and the exemplification of results of the Italian MSP process, this paper discusses the most relevant features and common challenges of multi-scalar MSP (i.e. co-planning, vertical and horizontal integration, multi-level governance, scalability, flexibility, integration of data and knowledge with different resolution, multi-scalar stakeholder engagement). Finally, the paper reflects on some novel aspects of the adopted multi-scalar approach and identifies actions to grant efficacy to this approach during the next phases of the Italian MSP proces