Biology subjects

Jaimovich, E.

Publications and source records attributed to Jaimovich, E..

3 recordsLinked to original sources

bioRxiv2025

Chemogenetic Mitochondrial H2O2 Generation Triggers Dose-Dependent Skeletal Muscle Wasting Signatures

Mitochondrial hydrogen peroxide (mtH2O2) has long been implicated in skeletal muscle atrophy, yet its direct role in vivo has remained unresolved due to methodological constraints. Here, we aimed to establish a chemogenetic platform for precise, compartment-specific induction of mtH2O2 in adult skeletal muscle and to investigate how graded redox stress impacts on muscle proteostasis in vivo. Using mitochondria-targeted D-amino acid oxidase (mtDAAO), we show that prolonged and/or high mtH2O2 exposure progressively activates proteolytic and denervation-associated pathways, culminating in myofiber damage and regeneration. Remarkably, even low exposure to mtH2O2 is sufficient to acutely suppress protein synthesis and induce disuse-like atrophy, without structural damage or overt oxidative stress. This approach provides a powerful in vivo framework to dissect subcellular redox-controlled signaling in muscle and identifies mtH2O2 as a modulator of muscle proteostasis, with therapeutic relevance for muscle-wasting conditions.

molecular biology↗

bioRxiv2024

Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1G93A (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2+ transients and reactive oxygen species (i.e., H2O2). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.

neuroscience↗

bioRxiv2019

Exercise-stimulated muscle ROS production and glucose uptake requires NADPH oxidase 2

Reactive oxygen species (ROS) act as intracellular compartmentalized second messengers mediating metabolic stress-adaptation. In skeletal muscle fibers, ROS have been suggested to stimulate glucose transporter 4 (GLUT4)-dependent glucose transport during artificially evoked contraction ex vivo but whether myocellular ROS production is stimulated by in vivo exercise to control metabolism is unclear. Here, we combined exercise in humans and mice with fluorescent dyes, genetically-encoded biosensors, and NADPH oxidase 2 (NOX2) loss-of-function models to demonstrate that NOX2 is the main source of cytosolic ROS during moderate-intensity exercise in skeletal muscle. Furthermore, two NOX2 loss-of-function mouse models lacking either p47phox or Rac1 presented striking phenotypic similarities, including greatly reduced exercise-stimulated glucose uptake and GLUT4 translocation. These findings indicate that NOX2 is a major myocellular ROS source regulating glucose transport capacity during moderate-intensity exercise.

physiology↗