Muscleblind-like 1 (MBNL1) is an alternative splicing factor involved in postnatal development of skeletal muscles and heart in humans and mice, and its deregulation is known to be pivotal in the onset and development of myotonic dystrophy (DM). In fact, in DM patients this protein is ectopically sequestered into intranuclear foci, thus compromising the regulation of the alternative splicing of several genes. However, despite the numerous biochemical and molecular studies, scarce attention has been paid to the intranuclear location of MBNL1 outside the foci, although previous data demonstrated that in DM patients various splicing and cleavage factors undergo an abnormal intranuclear distribution suggestive of impaired RNA processing. Interestingly, these nuclear alterations strongly remind those observed in sarcopenia i.e., the loss of muscle mass and function which physiologically occurs during ageing. On this basis, in the present investigation the ultrastructural localization of MBNL1 was analyzed in the myonuclei of skeletal muscles from healthy and DM patients as well as from adult and old (sarcopenic) mice, in the attempt to elucidate possible changes in its distribution and amount. Our data demonstrate that in both dystrophic and sarcopenic muscles MBNL1 undergoes intranuclear relocation, accumulating in its usual functional sites but also ectopically moving to domains which are usually devoid of this protein in healthy adults. This accumulation/delocalization could contribute to hamper the functionality of the whole splicing machinery, leading to a lower nuclear metabolic activity and, consequently, to a less efficient protein synthesis. Moreover, the similar nuclear alterations found in DM and sarcopenia may account for the similar muscle tissue features (myofibre atrophy, fiber size variability and centrally located nuclei), and, in general, for the aging-reminiscent phenotype observed in DM patients.

Muscleblind-like1 undergoes Ectopic relocation in the nuclei of skeletal muscles in myotonic dystrophy and sarcopenia.

MALATESTA, Manuela;COSTANZO, Manuela;Cisterna, Barbara;
2013

Abstract

Muscleblind-like 1 (MBNL1) is an alternative splicing factor involved in postnatal development of skeletal muscles and heart in humans and mice, and its deregulation is known to be pivotal in the onset and development of myotonic dystrophy (DM). In fact, in DM patients this protein is ectopically sequestered into intranuclear foci, thus compromising the regulation of the alternative splicing of several genes. However, despite the numerous biochemical and molecular studies, scarce attention has been paid to the intranuclear location of MBNL1 outside the foci, although previous data demonstrated that in DM patients various splicing and cleavage factors undergo an abnormal intranuclear distribution suggestive of impaired RNA processing. Interestingly, these nuclear alterations strongly remind those observed in sarcopenia i.e., the loss of muscle mass and function which physiologically occurs during ageing. On this basis, in the present investigation the ultrastructural localization of MBNL1 was analyzed in the myonuclei of skeletal muscles from healthy and DM patients as well as from adult and old (sarcopenic) mice, in the attempt to elucidate possible changes in its distribution and amount. Our data demonstrate that in both dystrophic and sarcopenic muscles MBNL1 undergoes intranuclear relocation, accumulating in its usual functional sites but also ectopically moving to domains which are usually devoid of this protein in healthy adults. This accumulation/delocalization could contribute to hamper the functionality of the whole splicing machinery, leading to a lower nuclear metabolic activity and, consequently, to a less efficient protein synthesis. Moreover, the similar nuclear alterations found in DM and sarcopenia may account for the similar muscle tissue features (myofibre atrophy, fiber size variability and centrally located nuclei), and, in general, for the aging-reminiscent phenotype observed in DM patients.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11562/577552
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