Biology subjects

GONDIN, J.

Publications and source records attributed to GONDIN, J..

4 recordsLinked to original sources

bioRxiv2026

c-MAF transduces motor neuron firing to sustain fast-glycolytic myofibers and neuromuscular junctions

This study examined how motoneuron activity influences transcription factor binding in mouse fast glycolytic Myh4+ muscle fibers. Single nucleus multiomics of innervated versus denervated tibialis anterior muscles revealed altered chromatin accessibility: SIX and c-MAF binding sites decreased while JUN, FOS, and RUNX1 sites increased in denervated Myh4+ myonuclei. c-MAF showed strong nuclear enrichment after 100 Hz stimulation and periods of increased motoneuron activity but was absent following denervation, establishing it as a primary readout of fast motoneuron firing. Genome-wide analysis demonstrated that c-MAF binding site spacing encodes functionally distinct muscle gene programs. Analysis of constitutive and inducible skeletal muscle-specific c-Maf mutants revealed that c-MAF loss caused region-specific MYH4+ fiber atrophy, MYH1/MYH2 fiber type shifts resembling ALS G93A mouse phenotypes, and progressive neuromuscular junction fragmentation with increased motoneuron terminal sprouting and ectopic reinnervation. These findings establish c-MAF as a critical mediator linking motoneuron activity to muscle gene regulation, fiber integrity, and neuromuscular junction maintenance in fast glycolytic fibers.

physiology↗

bioRxiv2025

Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle

ObjectiveSmall-molecule activators targeting the allosteric drug and metabolite (ADaM) site of AMPK enhance insulin-independent glucose uptake in skeletal muscle and lower glucose in preclinical models of hyperglycemia. The regulatory AMPK{gamma} subunit plays a central role in energy sensing. While the skeletal muscle-selective {gamma}3 isoform is essential for AMP/ZMP-induced glucose uptake, it is dispensable for ADaM site-binding activators. We hypothesized that the predominant {gamma}1 isoform is required for ADaM site activator-stimulated glucose uptake in skeletal muscle. MethodsSingle-nucleus RNA sequencing (snRNA-seq) was performed on mouse and human skeletal muscle mapping AMPK subunit isoform distribution across resident cell types. To determine {gamma} isoform-specific requirements for activator-stimulated glucose uptake, skeletal muscle-specific inducible AMPK{gamma}1/{gamma}3 double knockout (im{gamma}1-/-/{gamma}3-/-) and single knockout (im{gamma}1-/- and im{gamma}3-/-) mice were generated. Ex vivo glucose uptake was measured following treatment with AICAR (AMP-mimetic) or MK-8722 (ADaM site activator), and in vivo MK-8722-induced blood glucose lowering was assessed. ResultssnRNA-seq revealed distinct AMPK isoform distribution: {gamma}1 was ubiquitously expressed, whereas {gamma}3 was enriched in glycolytic myofibers in both mouse and human skeletal muscle. Ex vivo, glucose uptake stimulated by either AICAR or MK-8722 was abolished in im{gamma}1-/-/{gamma}3-/- muscle, and MK-8722-induced blood glucose lowering was significantly blunted in vivo. AICAR but not MK-8722-stimulated muscle glucose uptake was abolished in im{gamma}3-/-, whereas both activators fully retained effects on glucose uptake and glucose lowering in im{gamma}1-/- mice. ConclusionsWhile {gamma}1 predominates in stabilizing the AMPK2{beta}2{gamma}1 complex, it is dispensable for AMPK activator-stimulated glucose uptake in skeletal muscle, whether mediated via the nucleotide-binding or ADaM site.

biochemistry↗

bioRxiv2022

Cyclosporin A delays the terminal disease stage in Tfam KO mice without improving mitochondrial energy production

AO_SCPLOWBSTRACTC_SCPLOWMitochondrial myopathies are rare genetic disorders characterized by muscle weakness and exercise intolerance. Currently, no effective treatment exists for these myopathies. Interestingly, the pharmacological cyclophilin inhibitor cyclosporine A (CsA) extended lifespan and prevented loss of force and mitochondrial Ca2+ overload in muscle fibers in the skeletal muscle-specific Tfam knockout mouse model of lethal mitochondrial myopathy (Tfam KO). The unaffected expression of proteins involved in mitochondrial energy metabolism suggests that these improvements occurred without improvement in metabolism. In this study, we aimed at investigating the effects of four weeks of CsA administration on in vivo contractile function and mitochondrial energy production in Tfam KO mice. The treatment started before the terminal phase with severe muscle weakness and weight loss. Our results show that CsA treatment delayed progression into the terminal disease phase. This occurred without any obvious positive effects on mitochondrial energy production at rest or during fatigue induced by repeated contractions. In conclusion, cyclophilin inhibitors may have the potential of counteracting devastating muscle weakness in patients with mitochondrial myopathies most probably by preventing deleterious effects triggered by excessive mitochondrial Ca2+ uptake rather than by improving mitochondrial energy production.

pathology↗

bioRxiv2021

Individualized isometric neuromuscular electrical stimulation training promotes myonuclear accretion in mouse skeletal muscle

Skeletal muscle is a plastic tissue that adapts to exercise through fusion of muscle stem cells (MuSCs) with myofibers, a physiological process referred to as myonuclear accretion. However, it is still unclear whether myonuclear accretion is driven by increased mechanical loading per se, or occurs, at least in part, in response to exercise-induced muscle injury. Here, we developed a carefully monitored and individualized neuromuscular electrical stimulation (NMES) training protocol of the mouse plantar flexor muscles. Each NMES training session consisted of 80 isometric contractions at a submaximal mechanical intensity corresponding to ~ 15% of maximal tetanic force to avoid muscle damage. NMES trained mice were stimulated for 2 x 3 consecutive days separated by one day of rest, for a total of 6 sessions. Experiments were conducted on C57BL/6J and BALB/c males at 10-12 weeks of age. NMES led to a robust myonuclear accretion and higher MuSC content in gastrocnemius muscle of both mouse lines, without overt signs of muscle damage/regeneration or muscle hypertrophy or force improvement. This new mouse model of myonuclear accretion relying on the main function of skeletal muscles, i.e., force production in response to electrical stimuli, will be of utmost interest to further understand the role of MuSCs in skeletal muscle adaptations.

physiology↗