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G.P.195
Abstracts / Neuromuscular Disorders 24 (2014) 791–924 pathogenic heterozygous mutation (R333W). GLUT-1 Deficiency Syndrome (DS) is a rare encephalopathy, caused by impaired glucose transport into the brain, presenting with early-onset epilepsy, movement disorders, developmental delay and microcephaly but rhabdomyolysis has never been reported in similar cases. To better define the origin of recurrent exercise-induced rhabdomyolysis in the father, he underwent forearm ischemic test (normal), EMG (myopathic pattern) and muscle biopsy that evidenced unspecific changes. Muscle biochemical studies excluded the most common metabolic causes of recurrent rhabdomyolysis, but VLCAD gene analysis in the father showed two known heterozygous mutations (p.G185S and p.R385W) whereas his son carried only the p.G185S. Nowadays, it is evident that cases of “double trouble” are increasing and, when a known phenotype is accompanied by some atypical features, we should think of an alternative explanation of unusual presentations. http://dx.doi:10.1016/j.nmd.2014.06.270
AGING MUSCLE HOMEOSTASIS G.P.195 BMP signaling controls satellite cell dependent postnatal muscle growth C. Beley 1, E. Schirwis 1, E. Mouisel 2, S. Alonso-Martin 3, A. Rochat 3, L. Garcia 1, A. Ferry 3, F. Relaix 3, M. Schuelke 4, F. Le Grand 5, H. Amthor 1 1 Universite´ de Versailles Saint Quentin en Yvelines, Montigny-le-Bretonneux, France; 2 Universite´ Paul Sabatier, Toulouse, France; 3 Universite´ Pierre et Marie Curie, Paris, France; 4 Charite´ Universita¨tsmedizin Berlin, Berlin, Germany; 5 Institut Cochin, Paris, France Postnatal/juvenil muscle growth is achieved by both an increase in myofiber size and the addition of further myonuclei, whereas myofiber number does not increase further. Satellite cells are the resident muscle stem cells which proliferate in growing muscle to supply new myonuclei. Little is known of how satellite cell function is controlled during the postnatal/juvenil growth phase to permit correct muscle mass development and the generation of the adult satellite cell pool. We previously have shown that signaling by Bone morphogenetic proteins (BMP) regulates embryonic myogenesis by determining the entry of embryonic muscle precursors into differentiation. Here we demonstrate that this pathway also defines postnatal/juvenil muscle growth. We found that juvenile satellite cells express elements of the BMP signaling cascade such as BMP ligands, BMP receptor, and the intracellular BMP responsive element P-Smad1/5/8, showing that BMP signaling is active in these cells. Abrogating BMP signaling targeted to satellite cells in juvenile Rosa26-Lox-Stop-Lox-Smad6-IRES-GFP:Pax7CreERT2/+ mice decreased the pool of satellite cells and muscle fibres contained less myonuclei and were smaller than those from control mice. We show that blockade of BMP signaling decreased satellite cell proliferation and diminished the myonuclear recruitment during myofiber growth as the underlying cellular mechanism, and this severely retarded muscle growth. In addition, failure of satellite cell proliferation strongly reduced the final satellite cell reservoir in mature muscle. In conclusion, these results show that correct BMP signaling in satellite cells is required for satellite cell dependent myofiber growth and for the generation of the adult satellite cell pool. In future it will be of large interest to determine whether the BMP signaling pathway is altered in childhood neuromuscular disorders and whether this inflicts satellite cell dependent muscle growth. http://dx.doi:10.1016/j.nmd.2014.06.271
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G.P.196 Metabolic effects of the Compact myostatin T. Kocsis, J.A. Baan, L. Mendler, L. Dux, A. Keller-Pinter University of Szeged, University of Szeged, Szeged, Hungary The TGF-beta member myostatin is an important negative regulator of skeletal muscle mass, influencing systemic (e.g. carbohydrate) metabolism. Beyond the Smad2/3 mediated signaling events it regulates the PI3K/Akt pathway, which plays a central role in integrating of anabolic and catabolic responses. The Compact (Cmpt) mice carry a naturally occurring 12-bp deletion in the propeptide region of the myostatin precursor, and additional modifiers are involved in determining the full expression of the hypermuscular phenotype. The metabolic effects of the Cmpt mutation are poorly understood. According to our results, the absolute weight of the investigated hindlimb muscles and liver significantly increased in Cmpt animals compared to wild-type; however, the muscle weight/body weight ratio significantly increased and the liver weight/body weight ratio significantly decreased in Cmpts. The total glycogen and protein amount increased in Cmpt M. tibialis anterior, M. quadriceps femoris, M. gastrocnemius and liver samples. Western blot analysis revealed that the mutation resulted in increased level of phospho-Akt (Ser473) in both muscle and liver samples despite the presence of Cmpt myostatin, indicating the absence/reduced effect of myostatin. The glucose tolerance test revealed increased glucose uptake in peripheral tissues of Cmpts, and the hepatic gluconeogenesis decreased determined by pyruvate tolerance test. To further assess liver function the activity of alanine transaminase (ALT) was measured in vitro, the total liver ALT activity to body mass ratio significantly decreased in Cmpt animals. In conclusion, the Cmpt mutation results in systemic consequences; it has opposite effect on the relative weight and glycogen concentration of skeletal muscle and liver, influences liver function and increases the peripheral glucose uptake. http://dx.doi:10.1016/j.nmd.2014.06.272
G.P.197 Strongman syndrome: Clinical, pathological and genetic characterization of dominant herculean myalgic disorders T.C. Conte 1, M. Tetreault 1, M.J. Dicaire 1, S.M. Provost 2, N. Al-Bustani 1, B. Beland 1, M.P. Dube 2, V. Bolduc 1, M. Srour 3, E. O’Ferrall 1, J.P. Bouchard 4, G. Ravenscroft 5, N. Laing 5, P. Lamont 5, J. Mathieu 6, R.T. Hepple 7, B. Brais 1 1 Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; 2 Montreal Heart Institute, Universite de Montreal, Montreal, Quebec, Canada; 3 Montreal Children Hospital, McGill University, Montreal, Quebec, Canada; 4 CHUQ Enfant-Jesus, Quebec, Quebec, Canada; 5 Western Australia Institute for Medical Research, Perth, Australia; 6 CSSS de Jonquiere, Jonquiere, Quebec, Canada; 7 Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada Muscle mass and strength are variable traits in humans. Many French Canadians (FC) became international celebrities because of their exceptional strength. Though muscle hypertrophy has been associated in many mammals with myostatin mutations, to date only a single pediatric case has been reported in humans. Dominant pathological mutations in the CLCN1, SCN4A, CAV3, ATP2A1, LPIN1, LMNA and RYR1 gene have been known to lead to muscle hypertrophy in humans, in particular selective muscle hypertrophy in certain myopathies. These conditions are associated with either weakness or increased strength. We recruited a cohort of more than 115 cases belonging to more than 65 families of a heterogeneous dominant condition that we refer to as: “Strongman syndrome” (SM). In all families, the most affected case suffers from incapacitating myalgias with variable degree of muscle cramps, and they also have a personal and familial history of above average strength. On examination these
AGING MUSCLE HOMEOSTASIS G.P.195 BMP signaling controls satellite cell dependent postnatal muscle growth C. Beley 1, E. Schirwis 1, E. Mouisel 2, S. Alonso-Martin 3, A. Rochat 3, L. Garcia 1, A. Ferry 3, F. Relaix 3, M. Schuelke 4, F. Le Grand 5, H. Amthor 1 1 Universite´ de Versailles Saint Quentin en Yvelines, Montigny-le-Bretonneux, France; 2 Universite´ Paul Sabatier, Toulouse, France; 3 Universite´ Pierre et Marie Curie, Paris, France; 4 Charite´ Universita¨tsmedizin Berlin, Berlin, Germany; 5 Institut Cochin, Paris, France Postnatal/juvenil muscle growth is achieved by both an increase in myofiber size and the addition of further myonuclei, whereas myofiber number does not increase further. Satellite cells are the resident muscle stem cells which proliferate in growing muscle to supply new myonuclei. Little is known of how satellite cell function is controlled during the postnatal/juvenil growth phase to permit correct muscle mass development and the generation of the adult satellite cell pool. We previously have shown that signaling by Bone morphogenetic proteins (BMP) regulates embryonic myogenesis by determining the entry of embryonic muscle precursors into differentiation. Here we demonstrate that this pathway also defines postnatal/juvenil muscle growth. We found that juvenile satellite cells express elements of the BMP signaling cascade such as BMP ligands, BMP receptor, and the intracellular BMP responsive element P-Smad1/5/8, showing that BMP signaling is active in these cells. Abrogating BMP signaling targeted to satellite cells in juvenile Rosa26-Lox-Stop-Lox-Smad6-IRES-GFP:Pax7CreERT2/+ mice decreased the pool of satellite cells and muscle fibres contained less myonuclei and were smaller than those from control mice. We show that blockade of BMP signaling decreased satellite cell proliferation and diminished the myonuclear recruitment during myofiber growth as the underlying cellular mechanism, and this severely retarded muscle growth. In addition, failure of satellite cell proliferation strongly reduced the final satellite cell reservoir in mature muscle. In conclusion, these results show that correct BMP signaling in satellite cells is required for satellite cell dependent myofiber growth and for the generation of the adult satellite cell pool. In future it will be of large interest to determine whether the BMP signaling pathway is altered in childhood neuromuscular disorders and whether this inflicts satellite cell dependent muscle growth. http://dx.doi:10.1016/j.nmd.2014.06.271
875
G.P.196 Metabolic effects of the Compact myostatin T. Kocsis, J.A. Baan, L. Mendler, L. Dux, A. Keller-Pinter University of Szeged, University of Szeged, Szeged, Hungary The TGF-beta member myostatin is an important negative regulator of skeletal muscle mass, influencing systemic (e.g. carbohydrate) metabolism. Beyond the Smad2/3 mediated signaling events it regulates the PI3K/Akt pathway, which plays a central role in integrating of anabolic and catabolic responses. The Compact (Cmpt) mice carry a naturally occurring 12-bp deletion in the propeptide region of the myostatin precursor, and additional modifiers are involved in determining the full expression of the hypermuscular phenotype. The metabolic effects of the Cmpt mutation are poorly understood. According to our results, the absolute weight of the investigated hindlimb muscles and liver significantly increased in Cmpt animals compared to wild-type; however, the muscle weight/body weight ratio significantly increased and the liver weight/body weight ratio significantly decreased in Cmpts. The total glycogen and protein amount increased in Cmpt M. tibialis anterior, M. quadriceps femoris, M. gastrocnemius and liver samples. Western blot analysis revealed that the mutation resulted in increased level of phospho-Akt (Ser473) in both muscle and liver samples despite the presence of Cmpt myostatin, indicating the absence/reduced effect of myostatin. The glucose tolerance test revealed increased glucose uptake in peripheral tissues of Cmpts, and the hepatic gluconeogenesis decreased determined by pyruvate tolerance test. To further assess liver function the activity of alanine transaminase (ALT) was measured in vitro, the total liver ALT activity to body mass ratio significantly decreased in Cmpt animals. In conclusion, the Cmpt mutation results in systemic consequences; it has opposite effect on the relative weight and glycogen concentration of skeletal muscle and liver, influences liver function and increases the peripheral glucose uptake. http://dx.doi:10.1016/j.nmd.2014.06.272
G.P.197 Strongman syndrome: Clinical, pathological and genetic characterization of dominant herculean myalgic disorders T.C. Conte 1, M. Tetreault 1, M.J. Dicaire 1, S.M. Provost 2, N. Al-Bustani 1, B. Beland 1, M.P. Dube 2, V. Bolduc 1, M. Srour 3, E. O’Ferrall 1, J.P. Bouchard 4, G. Ravenscroft 5, N. Laing 5, P. Lamont 5, J. Mathieu 6, R.T. Hepple 7, B. Brais 1 1 Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; 2 Montreal Heart Institute, Universite de Montreal, Montreal, Quebec, Canada; 3 Montreal Children Hospital, McGill University, Montreal, Quebec, Canada; 4 CHUQ Enfant-Jesus, Quebec, Quebec, Canada; 5 Western Australia Institute for Medical Research, Perth, Australia; 6 CSSS de Jonquiere, Jonquiere, Quebec, Canada; 7 Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada Muscle mass and strength are variable traits in humans. Many French Canadians (FC) became international celebrities because of their exceptional strength. Though muscle hypertrophy has been associated in many mammals with myostatin mutations, to date only a single pediatric case has been reported in humans. Dominant pathological mutations in the CLCN1, SCN4A, CAV3, ATP2A1, LPIN1, LMNA and RYR1 gene have been known to lead to muscle hypertrophy in humans, in particular selective muscle hypertrophy in certain myopathies. These conditions are associated with either weakness or increased strength. We recruited a cohort of more than 115 cases belonging to more than 65 families of a heterogeneous dominant condition that we refer to as: “Strongman syndrome” (SM). In all families, the most affected case suffers from incapacitating myalgias with variable degree of muscle cramps, and they also have a personal and familial history of above average strength. On examination these