Histone Deacetylase Inhibitors in the Treatment of Muscular Dystrophies: Epigenetic Drugs for Genetic Diseases

Consalvi, Silvia; Saccone, Valentina; Giordani, Lorenzo; Minetti, Giulia; Mozzetta, Chiara; Puri, Prem

doi:10.2119/molmed.2011.00049

Cited by 75 publications

(62 citation statements)

References 86 publications

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“…For instance, miR-1 is regulated by MyoD and MEF2, which are also regulated by HDACs (26,27). Thus, by extension, HDAC inhibitors are predicted to promote the expression of myomiRs in myoblasts (28). In this report, we show that G␣i2 decreases the activity of HDACs in SCs; therefore, it is conceivable that the regulation of miR-1 by G␣i2 is also partly dependent on HDAC inhibition.…”

Section: Discussionmentioning

confidence: 54%

Gαi2 Signaling Is Required for Skeletal Muscle Growth, Regeneration, and Satellite Cell Proliferation and Differentiation

Minetti

Feige

Bombard

et al. 2014

Molecular and Cellular Biology

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eWe have previously shown that activation of G␣i2, an ␣ subunit of the heterotrimeric G protein complex, induces skeletal muscle hypertrophy and myoblast differentiation. To determine whether G␣i2 is required for skeletal muscle growth or regeneration, G␣i2-null mice were analyzed. G␣i2 knockout mice display decreased lean body mass, reduced muscle size, and impaired skeletal muscle regeneration after cardiotoxin-induced injury. Short hairpin RNA (shRNA)-mediated knockdown of G␣i2 in satellite cells (SCs) leads to defective satellite cell proliferation, fusion, and differentiation ex vivo. The impaired differentiation is consistent with the observation that the myogenic regulatory factors MyoD and Myf5 are downregulated upon knockdown of G␣i2. Interestingly, the expression of microRNA 1 (miR-1), miR-27b, and miR-206, three microRNAs that have been shown to regulate SC proliferation and differentiation, is increased by a constitutively active mutant of G␣i2 [G␣i2(Q205L)] and counterregulated by G␣i2 knockdown. As for the mechanism, this study demonstrates that G␣i2(Q205L) regulates satellite cell differentiation into myotubes in a protein kinase C (PKC)-and histone deacetylase (HDAC)-dependent manner. Heterotrimeric G proteins are intracellular proteins and transduce external signals from a variety of cell surface receptors to intracellular effectors (1). G proteins are classified according to their ␣ subunits into four subfamilies: G␣s, G␣i/o, G␣q/11, and G␣ 12/13 (1). The G␣i subfamily is encoded by three genes, GNAI1, GNAI2, and GNAI3, and was originally identified by its ability to inhibit adenylyl cyclase activity. All three G␣i isoforms have been deleted by gene targeting in mice, and the resulting phenotypes indicate that they have both overlapping and distinct functions. Ablation of G␣i1 in mice modulates adenylyl cyclase activity in the hippocampus and impairs memory formation (2). G␣i2-deficient mice display growth retardation, develop ulcerative colitis (3), and present defects of the parasympathetic heart rate (4), while G␣i3 has been shown to modulate insulin regulation of autophagy in hepatocytes (5) and to be required for normal patterning of the axial skeleton (6) and for cytoskeleton-dependent control of cilium migration as an important step in establishing planar cell polarity in cochlear cells (7). However, the requirement for G␣i isoforms in skeletal muscle growth and regeneration has not been determined.Mammalian skeletal muscle has the ability to regenerate and repair in response to exercise or injury. Regeneration of skeletal muscle is mainly executed by satellite cells (SCs) (8). SCs are a population of muscle stem cells that reside between the sarcolemma and the basal lamina. In neonatal muscle, growth is mainly achieved by addition of myoblasts derived from SCs to existing myofibers (9, 10). In the adult muscle, SCs-quiescent under normal physiological conditions-are activated in response to trauma and are able to self-renew, proliferate, and differentiate to fuse to damaged fibers or fo...

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Section: Discussionmentioning

confidence: 54%

Gαi2 Signaling Is Required for Skeletal Muscle Growth, Regeneration, and Satellite Cell Proliferation and Differentiation

Minetti

Feige

Bombard

et al. 2014

Molecular and Cellular Biology

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“…Animals without myostatin or treated with blocking agents have increased muscle mass, while people and animals with a myostatin gene mutation have more muscle mass and are stronger (Schuelke et al 2004;Grobet et al 1997). Blocking myostatin activity has some therapeutic application in treating muscle wasting diseases such as muscular dystrophy in mouse models and clinical trials, though has not been shown to be useful for sarcopenia (Smith and Lin 2013;Consalvi et al 2011;Benny Klimek et al 2010;Guasconi and Puri 2008;Wagner et al 2008). With recent molecular advances, it was hoped that High Throughput Screening methods, employed in the search for biologically active compounds which might attenuate muscular dystrophy, might also identify look-alike molecular pathways and drug targets in sarcopenia (Gintjee et al 2014).…”

Section: Exercise Frailty and Epigenetic Changementioning

confidence: 99%

Living long and ageing well: is epigenomics the missing link between nature and nurture?

2015

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Human longevity is a complex trait and increasingly we understand that both genes and lifestyle interact in the longevity phenotype. Non-genetic factors, including diet, physical activity, health habits, and psychosocial factors contribute approximately 50% of the variability in human lifespan with another 25% explained by genetic differences. Family clusters of nonagenarian and centenarian siblings, who show both exceptional age-span and health-span, are likely to have inherited facilitatory gene groups, but also have nine decades of life experiences and behaviours which have interacted with their genetic profiles. Identification of their shared genes is just one small step in the link from genes to their physical and psychological profiles. Behavioural genomics is beginning to demonstrate links to biological mechanisms through regulation of gene expression, which directs the proteome and influences the personal phenotype. Epigenetics has been considered the missing link between nature and nurture. Although there is much that remains to be discovered, this article will discuss some of genetic and environmental factors which appear important in good quality longevity and link known epigenetic mechanisms to themes identified by nonagenarians themselves related to their longevity. Here we suggest that exceptional 90-year old siblings have adopted a range of behaviours and life-styles which have contributed to their ageing-well-phenotype and which link with important public health messages.

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“…When zebrafish dmd mutant larvae are exposed to MG132, reduced muscle damage, as assessed by birefringence (see below Section 5.1 Assessing muscle structure), is observed [59]. In a second study, my laboratory tested the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA), because it and other HDAC inhibitors can ameliorate the mdx model [17,62,63]. We showed that TSA robustly rescues muscle fiber damage in the zebrafish dmd mutant [62].…”

Section: Pharmacological Therapies For Dmd Studied In Zebrafishmentioning

confidence: 99%

“…For DMD in particular, gene therapy and stem cell-mediated therapeutic strategies hold tremendous promise, but these approaches still face many obstacles [12,13]. Therefore, many different pharmacological therapies are currently being pursued [14-17]. One advantage of pharmacological therapy is that systemically delivered drugs could reach all muscle groups, including the heart, which undergoes cardiomyopathy in DMD patients [13-15].…”

Section: Introductionmentioning

confidence: 99%

Recent advances using zebrafish animal models for muscle disease drug discovery

Maves

2014

Expert Opinion on Drug Discovery

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Introduction Animal models have enabled great progress in the discovery and understanding of pharmacological approaches for treating muscle diseases like Duchenne muscular dystrophy. Areas covered With this article, the author provides the reader with a description of the zebrafish animal model, which has been employed to identify and study pharmacological approaches to muscle disease. In particular, the author focuses on how both large-scale chemical screens and targeted drug treatment studies have established zebrafish as an important model for muscle disease drug discovery. Expert opinion There are a number of opportunities arising for the use of zebrafish models for further developing pharmacological approaches to muscle diseases, including studying drug combination therapies and utilizing genome editing to engineer zebrafish muscle disease models. It is the author’s particular belief that the availability of a wide range of zebrafish transgenic strains for labeling immune cell types, combined with live imaging and drug treatment of muscle disease models, should allow for new elegant studies demonstrating how pharmacological approaches might influence inflammation and the immune response in muscle disease.

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Histone Deacetylase Inhibitors in the Treatment of Muscular Dystrophies: Epigenetic Drugs for Genetic Diseases

Cited by 75 publications

References 86 publications

Gαi2 Signaling Is Required for Skeletal Muscle Growth, Regeneration, and Satellite Cell Proliferation and Differentiation

Gαi2 Signaling Is Required for Skeletal Muscle Growth, Regeneration, and Satellite Cell Proliferation and Differentiation

Living long and ageing well: is epigenomics the missing link between nature and nurture?

Recent advances using zebrafish animal models for muscle disease drug discovery

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