Journal of Physiology-London最新文献

Disuse-induced skeletal muscle atrophy, commonly resulting from bedrest, immobilisation or spaceflight, leads to rapid loss of muscle mass and impaired mobility. Although muscle mass and contractile force are standard assessments in experimental models, these measures often fail to capture neuromuscular co-ordination deficits essential for effective movement. To better characterise these deficits, we employed a mouse hindlimb suspension (HLS) model for 14 days to induce disuse atrophy, confirmed by reductions in muscle mass, fibre type remodelling and satellite cell depletion, all of which were only partially reversed after a 7-day reloading period. In vivo analysis showed that gastrocnemius contractile force was significantly reduced following HLS and recovered incompletely after reloading. To functionally assess mobility, we implemented a non-invasive treadmill-based gait analysis, which revealed domain-specific impairments across neural control/rhythm, neuromuscular co-ordination and stability/variability, which were only partially restored after reloading, whereas muscle strength-related metrics such as paw drag showed mild but consistent alterations. At the molecular level, we identified elevated expression of MG29, subcellular redistribution of MG53 and altered expression of neuromuscular function-related genes (e.g. Ninj1, Prkg1, Ryr1 and S100a1), suggesting that MG29 and MG53 may contribute to impaired muscle plasticity and synaptic remodelling. Overall, our findings demonstrate that gait analysis can enhance the functional assessment of muscle disuse and recovery, offering a translational tool to evaluate interventions targeting atrophy-related mobility decline. KEY POINTS: Hindlimb suspension induces muscle atrophy and contractile loss, but functional consequences are not fully captured by traditional measurements. Gait analysis provides a non-invasive framework to evaluate neuromuscular performance across four domains: muscle strength/size, neural control/rhythm, neuromuscular co-ordination and stability/variability. Hindlimb suspension caused domain-specific impairments in rhythm control, co-ordination and stability, which were only partially restored after reloading, whereas strength-related metrics such as paw drag showed mild but consistent alterations. Correlation analyses revealed parallel reductions in propulsion- and rhythm-related gait metrics alongside decreases in muscle fibre size and tetanic force, indicating a functional-structural linkage between gait output and muscle integrity. Functional impairment is associated with satellite cell loss, MG29 upregulation, MG53 redistribution and neuromuscular function-related gene alteration. These findings identify gait metrics as biomarkers that may serve as early, non-invasive indicators of muscle disuse and recovery, providing mechanistic insights and a new tool to evaluate interventions targeting atrophy-related mobility loss.

Sudden cardiac death in young individuals with structurally normal hearts represents a critical unresolved clinical challenge and typically occurs in patients with inherited arrhythmia syndromes due to cardiac channelopathies. Catecholaminergic polymorphic ventricular tachycardia (CPVT) can cause fatal arrhythmias triggered by adrenergic stimulation. Therapeutic interventions primarily target cardiac myocytes (CMs) despite robust clinical evidence demonstrating the life-saving efficacy of cardiac sympathetic denervation. To understand this therapeutic paradox, we developed human induced pluripotent stem cell (hiPSC)-derived CMs and sympathetic neurons (SNs) from healthy individuals and CPVT patients to investigate neurocardiac interactions using two- and three-dimensional microtissue models. We tested the hypothesis that CPVT is also a disease of the autonomic nervous system and observed that CPVT hiPSC-derived SNs had enhanced calcium transients, elevated cyclic adenosine monophosphate levels, and hyperexcitability, similar to diseased cardiomyocytes. Critically, co-culturing diseased neurons with healthy CMs induced arrhythmogenic activity, establishing that neuronal dysfunction directly triggers cardiac arrhythmias. Multielectrode array recordings, optical mapping and single-cell RNA sequencing revealed dysregulated neurotransmitter pathways and identified druggable molecular targets within SNs. These findings may explain why surgically interrupting sympathetic nerves helps CPVT patients and identify the nervous system as a therapeutic target. They further suggest that CPVT is more than a disease of the CM and should be re-defined as a neuro-cardiac disorder that paves the way for neuromodulation therapy. KEY POINTS: Sympathetic nerve overactivity is pro-arrhythmic and a key contributor to ventricular tachycardia and sudden cardiac death in patients with cardiac channelopathies. Catecholaminergic polymorphic ventricular tachycardia (CPVT) sympathetic neurons (SNs) exhibit enhanced calcium transients, elevated cAMP levels, and hyperexcitability that directly trigger arrhythmias in healthy cardiomyocytes. Novel human induced pluripotent stem cell-derived cardiac-neural microtissue models reveal CPVT is also a neurological disorder involving dysfunctional neurocardiac interactions. Single-cell RNA sequencing identifies dysregulated neurotransmitter pathways in SNs, providing new therapeutic targets for neuromodulation therapy.