Biology subjects

Gondin, J.

Publications and source records attributed to Gondin, J..

4 recordsLinked to original sources

bioRxiv2026

NEUROMUSCULAR ELECTRICAL STIMULATION LIMITS MUSCLE WEAKNESS, ATROPHY, MODULATES SATELLITE CELL FUNCTION AND REDUCES INFLAMMATION IN CANCER CACHEXIA

BackgroundCancer cachexia (CC) is characterized by skeletal muscle atrophy and reduced strength, partly linked to dysfunction of muscle stem cells (MuSCs) and alterations in their niche. Although exercise may mitigate muscle loss, its effects in CC remain debated and its feasibility is often limited in advanced patients. Neuromuscular electrical stimulation (NMES) offers a promising alternative, by promoting MuSC proliferation and fusion, increasing muscle size and macrophage content in healthy muscle. This study investigated whether NMES, initiated at tumor onset, could improve MuSC regulation and its niche while limiting muscle atrophy and weakness in a tumor-bearing mouse model. MethodsTen-week-old male BALB/c mice were subcutaneously injected with C26 tumor cells or PBS. Tumor-bearing mice were divided into NMES-treated (C26 NMES) and non-stimulated controls (C26). NMES consisted of six sessions (two series of three consecutive daily sessions separated by one rest day), starting seven days post-inoculation when tumors became visible. Each session was delivered at a submaximal intensity corresponding to 15% of maximal strength. Muscle mass, myofiber size, strength and cellular composition were assessed. ResultsMuscle mass was decreased by 13% in C26 mice as compared to PBS controls, while C26 NMES mice showed a [~]7% improvement over C26 mice. Mean myofiber size decreased similarly in both tumor-bearing groups as compared to PBS controls (-12-14%). However, NMES reduced the proportion of small myofibers (400-600 {micro}m{superscript 2}) as compared to C26 mice. Maximal torque loss was less severe in C26 NMES mice (-28%) than in C26 mice (-34%). As compared with PBS mice, C26 mice exhibited increased MuSC proliferation (+97%) but reduced differentiation (-61%), as indicated by fewer myogenin-positive cells. NMES normalized MuSC proliferation, restored myogenin-positive cell number, and enhanced MuSC fusion, reflected by an increased number of PCM1-positive myonuclei (+8-11%). NMES also modulated inflammation, reducing neutrophils (-42%) and increasing macrophages (+35%), through the proliferation of CD169-positive resident macrophages (+106%). In vitro, macrophages exposed to C26 muscle extracts showed elevated pro-inflammatory markers (COX2 and TNF-; +21% and +16%) as compared to PBS controls. This effect was abolished with extracts from C26 NMES muscles. Additionally, C26 extracts reduced the expression of anti-inflammatory markers by macrophages (CD206 and IL-10; -23%), whereas NMES restored their levels to those of controls. ConclusionNMES-induced mild contractile activity is an effective stimulus for preserving muscle strength and mass, improving MuSC regulation, and modulating muscle inflammation in a mouse model of CC.

cell biology↗

bioRxiv2019

Muscle MACF1 maintains myonuclei and mitochondria localization through microtubules to control muscle functionalities

Skeletal muscle is made from multinuclear myofiber, where myonuclei are positioned at the periphery or clustered below neuromuscular junctions (NMJs). While mispositioned myonuclei are the hallmark of numerous muscular diseases, the molecular machinery maintaining myonuclei positioning in mature muscle is still unknown. Here, we identified microtubule-associated protein MACF1 as an evolutionary conserved regulator of myonuclei positioning, in vitro and in vivo, controlling the \"microtubule code\" and stabilizing the microtubule dynamics during myofibers maturation, preferentially at NMJs. Specifically, MACF1 governs myonuclei motion, mitochondria positioning and structure and acetylcholine receptors (AChRs) clustering. Macf1-KO in young and adult mice decreases muscle excitability and causes evolutionary myonuclei positioning alterations in adult mice, paralleled with high mitochondria content and improved resistance to fatigue. We present MACF1 as a primary actor of the maintenance of synaptic myonuclei and AChRs clustering, peripheral myonuclei positioning and mitochondria organization through the control of microtubule network dynamics in muscle fibers.

cell biology↗

bioRxiv2018

Annexin A1 drives macrophage skewing towards a resolving phenotype to accelerate the regeneration of muscle injury through AMPK activation

Understanding the circuits that promote an efficient resolution of inflammation is crucial to deciphering the molecular and cellular processes required to promote tissue repair. Macrophages play a central role in the regulation of inflammation, resolution and repair/regeneration. Using a model of skeletal muscle injury and repair, herein we identify Annexin A1 (AnxA1) as the extracellular trigger of macrophage skewing towards a pro-reparative phenotype. Brought into the injured tissue initially by migrated neutrophils, and then over-expressed in infiltrating macrophages, AnxA1 activates FPR2/ALX receptors and the downstream AMPK signalling cascade leading to macrophage skewing, dampening of inflammation and regeneration of muscle fibres. Mice lacking AnxA1 in all cells or in myeloid cells only display a defect in this reparative process. In vitro experiments recapitulated these properties, with AMPK null macrophages lacking AnxA1-mediated polarization. Collectively, these data identify the AnxA1/FPR2/AMPK axis as a novel pathway in skeletal muscle injury regeneration.

cell biology↗

bioRxiv2017

L-tyrosine supplementation is not therapeutic for skeletal muscle dysfunction in zebrafish and mouse models of dominant skeletal muscle α-actin nemaline myopathy.

Nemaline myopathy (NM) is a skeletal muscle disorder with no curative treatment. Although L-tyrosine administration has been indicated to provide benefit to patients, previous studies have been limited due to sample size or not testing for raised L-tyrosine levels. We evaluated the efficacy of L-tyrosine treatment to improve skeletal muscle function in three animal models of NM caused by skeletal muscle -actin (ACTA1) mutations. Firstly we determined the maximum safest L-tyrosine concentration for inclusion in the water of wildtype zebrafish. We then treated NM TgACTA1D286G-eGFP zebrafish from 24 hours post fertilization with the highest safe L-tyrosine dose (10 {micro}M). At 6 days post fertilization, no significant improvement was detected in skeletal muscle function (swimming distance). We also determined the highest safe L-tyrosine dose for dietary L-tyrosine supplementation to wildtype mice. Next we treated the NM TgACTA1D286G mouse model continuously from preconception with 2% L-tyrosine supplemented to regular feed. We examined skeletal muscles at 6-7 weeks using indicators of skeletal muscle integrity: bodyweight, voluntary running wheel and rotarod performance, all parameters previously shown to be reduced in TgACTA1D286G mice. The L-tyrosine treatment regime did not result in any improvement of these parameters, despite significant elevation of free L-tyrosine levels in sera (57%) and quadriceps muscle (45%) of treated TgACTA1D286G mice. Additionally, we assessed the effects of 4 weeks of 2% L-tyrosine dietary supplementation on skeletal muscle function of older (6-7 month old) NM TgACTA1D286G and KIActa1H40Y mice. This dosing regime did not improve decreased bodyweight, nor the mechanical properties, energy metabolism, or atrophy of skeletal muscles in these NM models. Together these findings demonstrate that with the treatment regimes and doses evaluated, L-tyrosine does not therapeutically modulate dysfunctional skeletal muscles in NM animal models with dominant ACTA1 mutations. Therefore this study yields important information on aspects of the clinical utility of L-tyrosine for ACTA1 NM.\n\nSummary statementDespite previous encouraging reports, this study utilising zebrafish and mouse models of nemaline myopathy shows no therapeutic benefit on skeletal muscle functionality in response to L-tyrosine supplementation.

neuroscience↗