Biology subjects

Lindsay, A.

Publications and source records attributed to Lindsay, A..

9 recordsLinked to original sources

bioRxiv2026

ADSS1 is a suppressed metabolic control node in dystrophic skeletal muscle

Duchenne muscular dystrophy is initiated by dystrophin loss but is accompanied by profound metabolic remodelling. Here, we identify suppression of the muscle-enriched adenylosuccinate synthase, ADSS1, and the purine nucleotide cycle in mdx muscle. Integrated multi-omic profiling revealed a compensated purine-stress state in which nucleotide salvage and quality control were increased to preserve adenine nucleotide abundance and buffer consequential toxic/disruptive deoxy-/nucleotide production. Purine metabolism was the highest-impact joint pathway with metabolite and transcript hits in mdx muscle, and its maintenance program was directionally conserved in human ADSS1 myopathy. Interventions positioned around ADSS1 separated the outputs of this node. Ribose and dimethyl fumarate remodelled upstream or downstream stress programs, whereas only adenylosuccinic acid bypassed ADSS1 to expand the adenine nucleotide pool and remodel CoA/acetyl-CoA metabolism. All three interventions suppressed pro-adipogenic transcription without broadly correcting the lipidome. These findings identify ADSS1 as a regulated metabolic control node that couples purine retention to inflammatory and adipogenic remodelling in dystrophic muscle.

molecular biology↗

bioRxiv2026

Deep brain stimulation reduces subthalamic nucleus pathological dynamics and rescues gait deficits associated with dopamine loss

The Subthalamic Nucleus (STN) regulates movement and is an important clinical target for deep brain stimulation (DBS) in Parkinsons Disease (PD). However, it remains unclear how dopamine loss and DBS influence STN gait encoding. We performed simultaneous recordings from multiple neurons and intermittent DBS in the STN of healthy and dopamine depleted PD mice during voluntary locomotion. We found that dopamine loss resulted in gait deficits manifested as altered stride length of both hindlimbs and forelimbs, which were rescued by intermittent DBS. Furthermore, dopamine loss exaggerated movement encoding of STN population dynamics, and elevates individual STN spiking during movement and beta-rhythmic firing at rest. Despite an overall increase in the fraction of neuron activated by movement, individual neurons gait encoding properties remain similar between healthy and PD mice. While DBS suppressed firing in both healthy and PD mice, it selectively reduced STN beta-rhythmic spiking, desynchronized STN networks, and rescued gait deficits associated with the loss of dopamine. These results suggest that pathological activation and beta synchronization of the STN contributes to motor deficits related to PD, and DBS-induced reduction of beta rhythmic spiking and STN network desynchronization contribute to the therapeutic effects of DBS in PD.

neuroscience↗

bioRxiv2026

Regimen-dependent glucocorticoid effects improve muscle performance without altering CNS physiology in mdx mice

Duchenne muscular dystrophy (DMD) is a multisystem disorder affecting striated muscle, metabolism, and the central nervous system (CNS). Although glucocorticoids remain the standard therapy, muscle-centric evaluations typically fail to capture how dosing regimen and compound selection affect CNS and metabolic phenotypes. Here, we compared daily and weekly dosing of prednisolone and vamorolone in juvenile mdx mice over six weeks to determine how these variables influence multisystem outcomes. Multiorgan efficacy and adverse effects were quantified across behavioural, endocrine, metabolic, cardiovascular, and muscle domains using behavioural assays, in vivo and functional muscle testing, haemodynamic evaluation and histopathology. Daily glucocorticoid dosing failed to improve muscle function or strength, whereas weekly vamorolone produced the most robust improvements in functional and in vivo muscle strength. Daily prednisolone reduced circulating creatine kinase levels, but this biochemical change did not translate into enhanced muscle function outcomes. Daily regimens also induced severe adrenal cortical atrophy, yet these endocrine alterations were dissociated from CNS stress and anxiety responses, which remained unchanged by treatment. In addition, daily dosing caused pronounced systemic metabolic consequences, whereas weekly regimens substantially attenuated these effects, identifying dosing frequency as a key determinant of safety. Together, these findings demonstrate that glucocorticoid regimen selection fundamentally reshapes the efficacy-adverse effect profile and underscores the value of integrated multiorgan evaluation in DMD. This work highlights the need to expand therapeutic assessments beyond muscle pathology and raises new questions about how glucocorticoid signalling differentially engages peripheral and central physiological systems.

physiology↗

bioRxiv2026

Endocrine-metabolic decoupling drives stress vulnerability in dystrophin deficiency

Skeletal muscle orchestrates systemic metabolism, dynamically coordinating glucose uptake and fuel use to match energy demand. In Duchenne muscular dystrophy, loss of dystrophin is associated with altered metabolic regulation. In the mdx mouse, we show that physiological stress reveals impaired coordination between insulin and stress responses: glucocorticoid signalling increases without a proportional rise in insulin secretion, resulting in systemic hyperglycaemia despite preserved capacity for muscle glucose uptake. These data support a multi-tissue dystrophinopathy associated with altered endocrine-metabolic coordination. Skeletal muscle glycogen is elevated and incompletely mobilised under stress. The heart maintains high glucose uptake, whereas the brain exhibits reduced uptake, highlighting tissue specific differences in metabolic response. Acute insulin supplementation improves systemic glucose control and restores stress-induced behavioural deficits. Likewise, empagliflozin-mediated glucose offloading reduces stress-associated blood glucose spikes and is associated with improved muscle function to levels comparable with standard care prednisolone. These findings identify impaired coordination of endocrine and metabolic responses during stress as a contributor to metabolic vulnerability in DMD and suggest that modulating insulin availability or glucose flux can improve systemic metabolic control.

systems biology↗

bioRxiv2025

Skeletal muscle TDP-43 aggregation drives progressive motor dysfunction and neurodegeneration with potential for functional recovery after clearance

Understanding the mechanisms driving TDP-43 pathology is essential for combating amyotrophic lateral sclerosis and other neurodegenerative diseases. To investigate the contribution of skeletal muscle to disease onset, progression, and recovery, we generated an inducible, muscle-specific TDP-43 mouse model. Cytoplasmic aggregation of exgogenous human TDP-43 protein in skeletal muscle led to muscle dysfunction, denervation, motor neuron loss, and dysregulation of mRNA markers related to myogenesis and neuromuscular junction stress at disease early-stage, along with muscle atrophy, neurodegeneration, and fatal motor decline at disease late-stage. Notably, this endogenous TDP-43 propagated from skeletal muscle to the spinal cord and brain, underscoring the vulnerability of the central nervous system to muscle-derived TDP-43 toxicity. Suppression of cytoplasmic TDP-43 in skeletal muscle improved survival and promoted substantial recovery of muscle dysfunction, motor deficits and neurodegeneration. These findings highlight the therapeutic potential of targeting skeletal muscle-derived TDP-43 toxicity as an approach to delaying neurodegenerative disease.

neuroscience↗

bioRxiv2025

Dystrophin-deficiency stiffens skeletal muscle and impairs elasticity: an in vivo rheological examination

Loss of dystrophin alters the biomechanical properties of skeletal muscle, including stiffness. Stiffness is typically assessed passively in excised muscle, but here we present the development of an in vivo rheological method to assess the mechanical properties of the tibialis anterior muscle in anaesthetised wild-type (WT; dystrophin-positive) and mdx (dystrophin-deficient) mice using a custom-designed apparatus compatible with an MCR 702 rheometer. To characterise stiffness, compressibility, and elasticity, rheological testing included compressive and shear strain protocols, along with recovery and assessments following contraction-induced strength loss. Relative to WT mice, the tibialis anterior of mdx mice were thicker, stiffer, and less compressible. These genotype differences aligned with hydroxyproline content, a marker of fibrosis. Post-deformation recovery was impaired in mdx mice under shear strain, and eccentric contraction-induced injury further increased stiffness and energy dissipation in the tibialis anterior of mdx mice. This rheological platform maintained the in vivo integrity of the tibialis anterior muscle of mice and consistently showed that storage and loss moduli can sensitively detect the detrimental impact of dystrophin-deficiency on the in vivo viscoelastic properties of skeletal muscle. This rheological platform, termed myomechanical profiling could be a viable and sensitive tool for assessing muscle quality and mechanical behaviour of skeletal muscle where viscoelastic properties are affected by disease.

physiology↗

bioRxiv2024

Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock-related protein Rbm20 in female mdx mice

Female carriers of a Duchenne muscular dystrophy (DMD) gene mutation manifest exercise intolerance and metabolic anomalies that may be exacerbated following menopause due to the loss of estrogen, a known regulator of skeletal muscle function and metabolism. Here, we studied the impact of estrogen depletion (via ovariectomy) on exercise tolerance and muscle mitochondrial metabolism in female mdx mice and the potential of estrogen replacement therapy (using estradiol) to protect against functional and metabolic perturbations. We also investigated the effect of estrogen depletion, and replacement, on the skeletal muscle proteome through an untargeted proteomic approach with TMT-labelling. Our study confirms that loss of estrogen in female mdx mice reduces exercise capacity, tricarboxylic acid cycle intermediates and citrate synthase activity but that these deficits can be offset through estrogen replacement therapy. Furthermore, ovariectomy downregulated protein expression of RNA binding motif factor 20 (Rbm20), a critical regulator of sarcomeric and muscle homeostasis gene splicing, which impacted pathways involving ribosomal and mitochondrial translation. Estrogen replacement modulated Rbm20 protein expression and promoted metabolic processes and the upregulation of proteins involved in mitochondrial dynamics and metabolism. Our data suggests that estrogen mitigates dystrophinopathic features in female mdx mice and that estrogen replacement may be a potential therapy for post-menopausal DMD carriers.

pathology↗

bioRxiv2023

Modulation of antigen discrimination by duration of immune contacts in a kinetic proofreading model of T cell activation with extreme statistics.

T cells form transient cell-to-cell contacts with antigen presenting cells (APCs) to facilitate surface interrogation by membrane bound T cell receptors (TCRs). Upon recognition of molecular signatures (antigen) of pathogen, T cells may initiate an adaptive immune response. The duration of the T cell/APC contact is observed to vary widely, yet it is unclear what constructive role, if any, such variations might play in immune signaling. Modeling efforts describing antigen discrimination often focus on steady-state approximations and do not account for the transient nature of cellular contacts. Within the framework of a kinetic proofreading (KP) mechanism, we develop a stochastic First Receptor Activation Model (FRAM) describing the likelihood that a productive immune signal is produced before the expiry of the contact. Through the use of extreme statistics, we characterize the probability that the first TCR triggering is induced by a rare agonist antigen and not by that of an abundant self-antigen. We show that defining positive immune outcomes as resilience to extreme statistics and sensitivity to rare events mitigates classic tradeoffs associated with KP. By choosing a sufficient number of KP steps, our model is able to yield single agonist sensitivity whilst remaining non-reactive to large populations of self antigen, even when self and agonist antigen are similar in dissociation rate to the TCR but differ largely in expression. Additionally, our model achieves high levels of accuracy even when agonist positive APCs encounters are rare. Finally, we discuss potential biological costs associated with high classification accuracy, particularly in challenging T cell environments. Author summaryPhysical contact between the T cell and antigen presenting cell (APC) is essential for productive immune signaling. Wide variations in this contact time have been observed yet little is known of mechanisms controlling this crucial timescale, nor how its duration may impact antigen discrimination. We develop and analyze a probabilistic mathematical model of T cell activation which combines kinetic proofreading (KP) with a finite contact duration. Our model is capable of suppressing large populations of self ligands while remaining sensitive to only a single agonist in T cell/APC cellular contacts. Additionally, we explored two challenging cases, one in which self and agonist antigen are similar and one in which agonist positive APCs are rare. We found that our model could overcome these environmental challenges by increasing the number of kinetic proofreading steps. Finally, we discuss the potential biological costs of achieving such accuracy. Our work demonstrates the extreme effectiveness of kinetic proofreading in a temporal context while also demonstrating the possible challenges in biological implementation of such a model.

systems biology↗

bioRxiv2021

T-cell microvilli simulations show operation near packing limit and impact on antigen recognition.

T-cells are immune cells that continuously scan for foreign-derived antigens on the surfaces of nearly all cells, termed antigen presenting cells (APCs). They do this by dynamically extending numerous protrusions called microvilli (MV) that contain T-cell receptors (TCRs) towards the APC surface in order to scan for antigens. The number, size, and dynamics of these MV, and the complex multi-scale topography that results, play a yet unknown role in antigen recognition. We develop an anatomically informed model of the T-cell/APC interface to elucidate the role of MV dynamics in antigen sensitivity and discrimination. We find that MV surveillance reduces antigen sensitivity compared to a completely flat interface unless MV are stabilized in an antigen-dependent manner and find that MV have only a modest impact on antigen discrimination. The model highlights that MV contacts optimise the competing demands of fast scanning speeds of the APC surface with antigen sensitivity and that T-cells operate their MV near the interface packing limit. Finally, we find that observed MV contact lifetimes can be largely influenced by conditions in the T-cell/APC interface with these lifetimes often being longer than the simulation or experimental observation period. The work highlights the role of MV in antigen recognition. Significance StatementT-cells search for foreign-derived antigens on the surface of antigen presenting cells (APC) by dynamically extending tubular protrusions called microvilli (MV) which form membrane close-contacts. Although known for decades, their role in antigen recognition remains unclear. Guided by recent experiments, we built an anatomically informed stochastic model of MV scanning and compared with a topologically flat interface. We find that MV scanning modestly impacts antigen discrimination, yet it enables T-cells to balance the competing effects of maintaining sensitivity while conducting rapid APC surveillance. The model can reconcile discrepancies in observed MV lifetimes and demonstrates that observed area coverage fractions correspond to geometric packing limits. Our work suggests that MVs promote positive signaling outcomes despite anatomical constraints to close contact formation.

biophysics↗