Biology subjects

Boyer, J. G.

Publications and source records attributed to Boyer, J. G..

3 recordsLinked to original sources

bioRxiv2025

A phenotypic screen identified KEAP1-kelch domain blockade as a mechanism to restore cardiac function in the setting of chronic severe hemodynamic stress

A bespoke gene expression (GE) based small molecule screen in human induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) was conducted with the aim of identifying drug targets and pathways with the potential to reverse heart failure (HF) pathologic GE and the resultant decompensated HF phenotype. The screen utilized a composite human-murine HF gene expression signature, a target annotated compound set, and a HF gene expression reversal scoring algorithm to identify small molecules and their associated targets as potential modulators of HF pathologic GE. Following hit triage, a lead optimization program, and compound characterization in preclinical rodent models of HF and human iPSC-CM contractility assays, KEAP1 kelch domain blockers were identified as potent efficacious agents in the restoration of contractile function in the setting of oxidant stress and pressure overload induced cardiac dysfunction.

molecular biology↗

bioRxiv2019

Satellite cell depletion in early adulthood attenuates muscular dystrophy pathogenesis

Satellite cells are skeletal muscle resident stem cells that regenerate adult myofibers following an acute injury to muscle. Despite the assumption that the loss of satellite cells would be detrimental in a chronic regeneration-inducing muscle disease such as muscular dystrophy, this assumption has never been tested using mouse genetics. Here we generated a novel model of satellite cell ablation and crossed it with mouse models of muscular dystrophy to directly investigate how critical these cells are in maintaining muscle during a chronic degenerative disorder. Satellite cell deletion in 2-week-old young dystrophic mice provided noticeable improvements in histopathology and function, although at this early timepoint it was utimately detrimental because muscle size was not sufficient to permit survival. However, depletion of satellite cells beginning at 2 months of age in dystrophic mice provided similar histological and functional improvements but without compromising muscle size. The improved profile showed fewer damaged fibers, less myofiber central nucleation, increased sarcolemma integrity, decreased fibrosis and a dramatic size increase in the remaining myofibers. At the functional level, young adult dystrophic mice lacking satellite cells performed significantly better than those with satellite cells when exercised on a treadmill. Thus, loss of satellite cells during early adulthood in dystrophic mice produces an unexpected protective effect.

molecular biology↗

bioRxiv2018

Mitogen-Activated Protein Kinase-Dependent Fiber-Type Regulation in Skeletal Muscle

Mitogen-activated protein kinases (MAPK) are conserved protein kinases that regulate a diverse array of cellular activities. Stress or mitogenic signals activate three primary branches of the greater MAPK cascade, each of which consists of a phosphorylation-dependent array of successively acting kinases. The extracellular signal-regulated kinase 1/2 (ERK1/2) branch is regulated by growth factory signaling at the cell membrane, leading to phosphorylation of the dual-specificity kinase MEK1, which is dedicated to ERK1/2 phosphorylation. Previous studies have established a link between MAPK activation and endurance exercise, but whether a single MAPK is responsible for establishing muscle metabolic fate is unclear. Using mouse genetics we observed that muscle-specific expression of a constitutively active MEK1 promotes greater ERK1/2 signaling that mediates fiber-type switching in mouse skeletal muscle to a slow, oxidative phenotype with type I myosin heavy chain expression. Induced expression of the activated MEK1 mutant using either a MyoD-Cre or myosin light chain-Cre strategy equally increased the number of type I fibers in skeletal muscle with significantly reduced size compared to controls. Moreover, activation of MEK1 in mature myofibers of an adult mouse using a transgene containing a tamoxifen inducible MerCreMer cDNA under the control of a skeletal -actin promoter produced a similar phenotype of switching towards a slow-oxidative program. Physiologic assessment of mice with greater skeletal muscle slow-oxidative fibers showed enhanced metabolic activity and oxygen consumption with greater fatigue resistance of individual muscles. In summary, these results show that sustained MEK1-ERK1/2 activity in skeletal muscle produces a fast-to-slow fiber-type switch, suggesting that modulation of this signaling pathway may represent a therapeutic approach to enhance the long-term metabolic effectiveness of muscle in vivo.

developmental biology↗