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- Lindqvist, Johan, et al.
(författare)
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Modulating Myosin Restores Muscle Function in a Mouse Model of Nemaline Myopathy
- 2016
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 79:5, s. 717-725
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Nemaline myopathy, one of the most common congenital myopathies, is associated with mutations in various genes including ACTA1. This disease is also characterized by various forms/degrees of muscle weakness, with most cases being severe and resulting in death in infancy. Recent findings have provided valuable insight into the underlying pathophysiological mechanisms. Mutations in ACTA1 directly disrupt binding interactions between actin and myosin, and consequently the intrinsic force-generating capacity of muscle fibers. ACTA1 mutations are also associated with variations in myofiber size, the mechanisms of which have been unclear. In the present study, we sought to test the hypotheses that the compromised functional and morphological attributes of skeletal muscles bearing ACTA1 mutations (1) would be directly due to the inefficient actomyosin complex and (2) could be restored by manipulating myosin expression.Methods: We used a knockin mouse model expressing the ACTA1 His40Tyr actin mutation found in human patients. We then performed in vivo intramuscular injections of recombinant adeno-associated viral vectors harboring a myosin transgene known to facilitate muscle contraction.Results: We observed that in the presence of the transgene, the intrinsic force-generating capacity was restored and myofiber size was normal.Interpretation: This demonstrates a direct link between disrupted attachment of myosin molecules to actin monomers and muscle fiber atrophy. These data also suggest that further therapeutic interventions should primarily target myosin dysfunction to alleviate the pathology of ACTA1-related nemaline myopathy.
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| 2. |
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| 3. |
- Winbanks, Catherine E., et al.
(författare)
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The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass
- 2013
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Ingår i: Journal of Cell Biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 203:2, s. 345-357
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Tidskriftsartikel (refereegranskat)abstract
- Although the canonical transforming growth factor. signaling pathway represses skeletal muscle growth and promotes muscle wasting, a role in muscle for the parallel bone morphogenetic protein (BMP) signaling pathway has not been defined. We report, for the first time, that the BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling. In agreement, we observed that BMP signaling is augmented in models of muscle growth. Importantly, stimulation of BMP signaling is essential for conservation of muscle mass after disruption of the neuromuscular junction. Inhibiting the phosphorylation of Smad1/5 exacerbated denervation-induced muscle atrophy via an HDAC4-myogenin-dependent process, whereas increased BMP-Smad1/5 activity protected muscles from denervation- induced wasting. Our studies highlight a novel role for the BMP signaling pathway in promoting muscle growth and inhibiting muscle wasting, which may have significant implications for the development of therapeutics for neuromuscular disorders.
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