[Ca.sup.2+]/calmodulin-based signalling in the regulation of the muscle fibre phenotype and its therapeutic potential via modulation of utrophin A and myostatin expression

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Publisher: NRC Research Press
Document Type: Article
Length: 6,055 words
Lexile Measure: 1710L

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Abstract: [Ca.sup.2+] signalling plays an important role in excitation-contraction coupling and the resultant force output of skeletal muscle. It is also known to play a crucial role in modulating both short- and long-term muscle cellular phenotypic adaptations associated with these events. [Ca.sup.2+] signalling via the [Ca.sup.2+]/calmodulin (CaM)-dependent phosphatase calcineurin (CnA) and via [Ca.sup.2+]/CaM-dependent kinases, such as CaMKI and CaMKII, is known to regulate hypertrophic growth in response to overload, to direct slow versus fast fibre gene expression, and to contribute to mitochondrial biogenesis. The CnA- and CaMK-dependent regulation of the downstream transcription factors nuclear factor of activated T cells (NFAT) and myocyte-specific enhancer factor 2 are known to activate muscle-specific genes associated with a slower, more oxidative fibre phenotype. We have also recently shown the expression of utrophin A, a cytoskeletal protein that accumulates at the neuromuscular junction and plays a role in maturation of the postsynaptic apparatus, to be regulated by CnA-NFAT and [Ca.sup.2+]/CaM signalling. This regulation is fibre-type specific and potentiated by interactions with the transcriptional regulators and coactivators GA binding protein (also known as nuclear respiratory factor 2) and peroxisome proliferatoractivated receptor-gamma coactivator 1 alpha. Another downstream target of CnA signalling may be myostatin, a transforming growth factor-[beta] family member that is a negative regulator of muscle growth. While the list of the downstream targets of CnA/NFAT- and [Ca.sup.2+]/CaM-dependent signalling is emerging, the precise interaction of these pathways with the [Ca.sup.2+]-independent pathways p38 mitogen-activated protein kinase, extracellular signal-regulated kinases 1 and 2, phosphoinositide-3 kinase, and protein kinase B (Akt/PKB) must also be considered when deciphering fibre responses and plasticity to altered contractile load.

Key words: calcineurin, CaMK, gene expression, muscular dystrophy, activity.

Resume: Le [Ca.sup.2+] joue, par son signal, un role important dans le processus de couplage electromecanique et dans la manifestation de la force du muscle squelettique. On sait aussi que cet ion joue un role crucial dans les adaptations cellulaires phenotypiques a court et a long terme de ce processus. La signalisation du [Ca.sup.2+] effectuee par l'action de la calcineurine (CnA), une phosphatase dependante de la calmoduline (CaM) et par les kinases dependantes du complexe calcium/ calmoduline, le CaMKI et le CaMKII, contribue a la regulation de l'hypertrophie en reponse a la surcharge, a l'expression des genes des fibres lentes ou des fibres rapides et a la biogenese de la mitochondrie. Les facteurs nucleaires des lymphocytes T (NFAT) et de rehaussement des myocytes (MEF2), facteurs de transcription en aval CnA- et CaMK-dependants, activent des genes specifiques associes au phenotype des fibres lentes a forte capacite oxydative. Nous avons aussi demontre recemment que les signaux emis par CnA/NFAT et [Ca.sup.2+]/CaM jouaient un role dans la regulation de l'expression de l'utrophine A, une proteine du cytosquelette s'accumulant a la jonction neuromusculaire et impliquee dans la maturation de l'appareil postsynaptique. Cette regulation, potentiee par des interactions des regulateurs transcriptionnels et des coactivateurs GABP (aussi appeles NRF2) et PGC-1a, est specifique au type de fibres musculaires. Il y a probablement une autre cible visee par la CnA, la myostatine,...

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Gale Document Number: GALE|A176688492