Stage-specific modulation of skeletal myogenesis by inhibitors of nuclear deacetylases

Abstract

Nuclear acetyltransferases promote and deacetylases inhibit skeletal muscle-gene expression, suggesting the potential effectiveness of deacetylase inhibitors (DIs) in modulating skeletal myogenesis. Surprisingly, previous studies have indicated that DIs suppress myogenesis. The recent observations that histone deacetylases associate with the muscle-regulatory proteins MyoD and MEF2C only in undifferentiated myoblasts prompted us to evaluate the effect of DIs at distinct stages of the myogenic program. We found that exposure of established rodent and human muscle cells to distinct DIs has stage-specific effects. Exposure of undifferentiated skeletal myoblasts to DIs, followed by incubation in differentiation medium, enhanced the expression of muscle-specific reporters and increased the levels of endogenous muscle proteins, leading to a dramatic increase in the formation of multinucleated myotubes. By contrast, simultaneous exposure of muscle cells to differentiation medium and DIs inhibited the myogenic program. Likewise, embryos exposed in utero to nonteratogenic doses of DI at the early stages of somitic myogenesis (embryonic day 8.5) exhibited an increased number of somites and augmented expression of a muscle-specific transgene as well as endogenous muscle genes. The functional effects induced by DIs were mirrored by changes in the state of acetylation of histones present at a muscle-gene enhancer and of MyoD itself. These results represent the first evidence that DIs can enhance muscle differentiation and suggest the rationale for their use in manipulating adult and embryonic skeletal myogenesis.deacetylase inhibitors ͉ gene expression ͉ MyoD ͉ skeletal muscle differentiation ͉ embryos

Acetylation of GATA-4 Is Involved in the Differentiation of Embryonic Stem Cells into Cardiac Myocytes

“…In contrast, it has been reported that TSA inhibits the differentiation of adipocytes (22) or oligodendrocytes (23). In the skeletal muscle cell lineage, TSA either augments or inhibits the differentiation depending on the developmental stage (24). These findings suggest that TSA has differential effects in distinct cell types or developmental stages.…”

Preclinical Studies in the mdx Mouse Model of Duchenne Muscular Dystrophy with the Histone Deacetylase Inhibitor Givinostat

“…Concentrations ranging from 80 to 200 nmol/L promoted the formation of myosin-heavy chain (MyHC)-positive multinucleated myotubes with a size larger than those formed by controltreated myoblasts-an effect that was equivalent to that observed with previously tested HDACi, such as TSA (Figure 1) (14). The potential availability of givinostat in clinical practice, and the known pharmacological profile of givinostat in pediatric patients (15), prompted an interest in testing givinostat in preclinical studies for the treatment of DMD.…”

Sulforaphane causes a major epigenetic repression of myostatin in porcine satellite cells

“…21 For TSA, we used the general concentration of 50 nM in accordance with previous reports, to serve as a positive control. 22,23 Almost all of the satellite cells were not viable after treatment at day 2 (data not shown); therefore, we selected day 3 (the myoblast stage) to start the treatment. To examine the cytotoxic effects of SFN, TSA and 5-aza-dC treatments on porcine satellite cell growth, we determined cell viability (Fig.…”