The endosomal escape vehicle platform enhances delivery of oligonucleotides in preclinical models of neuromuscular disorders.

Biological therapeutic agents are highly targeted and potent but limited in their ability to reach intracellular targets. These limitations often necessitate high therapeutic doses and can be associated with less-than-optimal therapeutic activity. One promising solution for therapeutic agent delivery is use of cell-penetrating peptides.

A cell-penetrating peptide enhances delivery and efficacy of phosphorodiamidate morpholino oligomers in mice.

Antisense RNA technology is a strategy for the treatment of Duchenne muscular dystrophy (DMD), a progressive and universally fatal X-linked neuromuscular disease caused by frameshift mutations in the gene encoding dystrophin. Phosphorodiamidate morpholino oligomers (PMOs) are an antisense RNA platform that is used clinically in patients with DMD to facilitate exon skipping and production of an internally truncated, yet functional, dystrophin protein. Peptide-conjugated PMOs (PPMOs) are a next-generation platform in which a cell-penetrating peptide is conjugated to the PMO backbone, with the goal of increasing cellular uptake.

MEF2D deficiency in neonatal cardiomyocytes triggers cell cycle re-entry and programmed cell death in vitro.

The cardiomyocyte cell cycle is a poorly understood process. Mammalian cardiomyocytes permanently withdraw from the cell cycle shortly after birth but can re-enter the cell cycle and proliferate when subjected to injury within a brief temporal window in the neonatal period. Thus, investigating the mechanisms of cell cycle regulation in neonatal cardiomyocytes may provide critical insight into the molecular events that prevent adult myocytes from proliferating in response to injury or stress.

MEF2 transcription factors regulate distinct gene programs in mammalian skeletal muscle differentiation.

Skeletal muscle differentiation requires precisely coordinated transcriptional regulation of diverse gene programs that ultimately give rise to the specialized properties of this cell type. In Drosophila, this process is controlled, in part, by MEF2, the sole member of an evolutionarily conserved transcription factor family. By contrast, vertebrate MEF2 is encoded by four distinct genes, Mef2a, -b, -c, and -d, making it far more challenging to link this transcription factor to the regulation of specific muscle gene programs.

Transcriptional networks regulating the costamere, sarcomere, and other cytoskeletal structures in striated muscle.

Structural abnormalities in striated muscle have been observed in numerous transcription factor gain- and loss-of-function phenotypes in animal and cell culture model systems, indicating that transcription is important in regulating the cytoarchitecture. While most characterized cytoarchitectural defects are largely indistinguishable by histological and ultrastructural criteria, analysis of dysregulated gene expression in each mutant phenotype has yielded valuable information regarding specific structural gene programs that may be uniquely controlled by each of these transcription factors. Linking the formation and maintenance of each subcellular structure or subset of proteins within a cytoskeletal compartment to an overlapping but distinct transcription factor cohort may enable striated muscle to control cytoarchitectural function in an efficient and specific manner.

MEF2A regulates the Gtl2-Dio3 microRNA mega-cluster to modulate WNT signaling in skeletal muscle regeneration.

Understanding the molecular mechanisms of skeletal muscle regeneration is crucial to exploiting this pathway for use in tissue repair. Our data demonstrate that the MEF2A transcription factor plays an essential role in skeletal muscle regeneration in adult mice. Injured Mef2a knockout mice display widespread necrosis and impaired myofiber formation.

Perceptual variation in umami taste and polymorphisms in TAS1R taste receptor genes.

Background: The TAS1R1 and TAS1R3 G protein-coupled receptors are believed to function in combination as a heteromeric glutamate taste receptor in humans.

Objective: We hypothesized that variations in the umami perception of glutamate would correlate with variations in the sequence of these 2 genes, if they contribute directly to umami taste.

Design: In this study, we first characterized the general sensitivity to glutamate in a sample population of 242 subjects.