Biology subjects

Atherton, P.

Publications and source records attributed to Atherton, P..

8 recordsLinked to original sources

bioRxiv2026

Acute caffeine ingestion differentially alters motor unit behaviour during submaximal and fatiguing contractions

Background: Caffeine is widely used as an ergogenic aid, yet its effect on neuromuscular function remains heterogeneous across exercise conditions. Although caffeine is known to enhance central nervous system excitability through adenosine receptor antagonism, the extent to which these effects modify spinal motor output remains unclear. Therefore, the present study aimed to characterise acute caffeine-induced alterations in neuromuscular properties during submaximal and sustained fatiguing contractions of the knee extensors. Methods: Seventeen healthy adults completed a randomised, placebo-controlled crossover study (3 mg/kg caffeine). Circulating serum caffeine concentrations were periodically quantified, while motor unit (MU) discharge behaviour, and delta F were derived from high-density surface electromyography. Statistical significance was set at p = 0.05. Results: No intervention effects were observed for MVC, force steadiness, or time to task failure (all p > 0.05). During graded contractions, vastus lateralis MU discharge rate was higher under caffeine (p < 0.001), and discharge variability was lower (p = 0.016). Recruitment and derecruitment thresholds were significantly greater under caffeine at 50% MVC (both p < 0.012), whereas paired MU analyses of delta F was unchanged (p = 0.083). During sustained contractions, caffeine altered fatigue-related trajectories of both MU discharge and discharge variability (intervention * phase interaction, p < 0.011). Conclusions: Acute caffeine ingestion alters motor unit behaviour without enhancing maximal force or fatigue resistance. These effects vary with contraction intensity and fatigue state but are not accompanied by a detectable change in discharge rate hysteresis in the vastus lateralis.

physiology↗

bioRxiv2026

Cell-matrix mechanosensing and cellular metabolic demand are linked through SKT and mTORC2

Integrin-based adhesion complexes mediate cell adhesion to the extracellular matrix and enable the cell to interpret and respond to both biochemical and mechanical cues. Such cues can affect a cells metabolic rate; however, how mechanical signals are converted into metabolic rate changes is not clear. We identified an uncharacterised protein; Sickle Tail Protein Homolog (KIAA1217), SKT to be enriched in cell-matrix adhesion complexes in stiff microenvironments. Low SKT expression correlates with an improved prognosis in pancreatic ductal adenocarcinoma (PDAC), suggesting an important role for SKT in extracellular matrix dependent tumour progression. Here, we show that SKT interacts with the mechanistic target of rapamycin complex 2 (mTORC2), a pivotal signalling complex in glucose metabolism, cell growth, and survival. SKT recruits mTORC2 to cell-matrix adhesions in a mechanoresponsive manner. SKT mediated mTORC2 signalling from adhesions is required for maintaining glycolytic flux and control of adhesion dynamics. Our findings show that SKT serves as a rheostat that controls metabolic adaptation of cells to their matrix microenvironment. Collectively, our research provides insights into the molecular mechanisms and interplay between cell adhesion and metabolic signalling in complex and stiff tumour microenvironments. The novel functions identified for SKT in cell-matrix adhesions, mTORC2 signalling and glycolysis unveils a signalling axis between the tumour microenvironment and cellular metabolism that are required for PDAC growth and invasion.

cell biology↗

bioRxiv2025

Bilateral neuromuscular adaptation to acute unilateral resistance exercise in healthy older adults

IntroductionResistance exercise (RE) enhances functionality in older adults and has proven effective as a means of cross-education in scenarios of unilateral disuse. However, the extent to which older adults demonstrate cross-limb transfer at the motor unit (MU) level following a single bout of unilateral RE is unclear. MethodsThirteen healthy older adults (74.9 {+/-} 4.8 years; 5 females) underwent bilateral neuromuscular assessments pre- and post- a single bout of unilateral RE consisting of 3-4 sets of 8-12 repetitions of leg extension of the dominant (exercise) leg, at 75% of 1 repetition maximum, performed to failure. Maximum voluntary contraction (MVC) and force steadiness (FS) were measured. Central and peripheral features of individual MU were recorded using high-density surface electromyography and intramuscular electromyography (HDs/iEMG), during contractions normalised to 25% MVC. ResultsFollowing unilateral RE, MVC reduced in exercise (-14.8%, p < 0.001) and control (-6.9%, p = 0.003) legs, with reduced FS performance in the exercise leg compared to the control (p = 0.002). MU firing rate increased during contractions normalised to 25% baseline MVC in the exercised leg (p < 0.05), with no adaptation in the control leg (p > 0.05). All iEMG recorded measures of MU potentials remained unchanged in both legs (all p > 0.05). ConclusionAcute unilateral RE leads to bilateral MVC reduction in older males and females, demonstrating the cross-limb transfer effect. However, adaptation of MU features was only apparent in the exercised limb, and mechanisms underlying the force decline in the non- exercised limb remain uncertain.

physiology↗

bioRxiv2024

Caskin2 is a novel talin and Abi1-binding protein that promotes cell motility

Talin couples the actomyosin cytoskeleton to integrins and transmits tension to the extracellular matrix. Talin also interacts with numerous additional proteins capable of modulating the actin-integrin linkage and thus downstream mechanosignaling cascades. Here, we demonstrate that the scaffold protein Caskin2 interacts directly with the R8 domain of talin through its C-terminal LD motif. Caskin2 also associates with the WAVE Regulatory Complex to promote cell migration in an Abi1-dependent manner. Furthermore, we demonstrate that the Caskin2-Abi1 interaction is regulated by growth factor-induced phosphorylation of Caskin2 on serine 878. In MCF7 and UACC893 cells, which contain an amplification of CASKIN2, Caskin2 localizes in plasma membrane-associated plaques and around focal adhesions in CMSCs. Taken together, our results identify Caskin2 as a novel talin-binding protein that may not only connect integrin-mediated adhesion to actin polymerization, but could also play a role in crosstalk between integrins and microtubules.

cell biology↗

bioRxiv2023

Sex disparities in age-related neuromuscular decline: unveiling female susceptibility from early to late elderly

BackgroundFemales typically have a longer lifespan than males which is not matched by an improved healthspan, with older females having higher rates of frailty, characteristic of a sex specific degradation of the neuromuscular system. Several motor unit (MU) characteristics show sex-specific behaviour during mid-level contractions in healthy younger people, highlighting a potential influence of hormonal differences that may be augmented in older age. The purpose of this study was to investigate sex differences in physical performance and MU features of the aged human vastus lateralis (VL) from early to late elderly. MethodsThis study included 21 healthy older males (mean {+/-} SD, range: 67.2 {+/-} 7.6, 56 - 81 yrs) and 17 healthy older females (69.5 {+/-} 5.2, 60 - 78 yrs). Intramuscular electromyography data were collected from VL during standardised submaximal sustained contractions. Muscle size and physical performance characteristics were also measured. Multiple mixed-effects linear regression models with age considered were conducted and statistical significance was accepted when p<0.05. ResultsWhen compared to males, early to late elderly females had smaller cross-sectional area of VL (p<0.001), lower knee extensor torque (p<0.001) and poorer force steadiness (p=0.036), as well as higher MU firing rate (FR) (p=0.025) and greater MU FR variability (p=0.031). With progression from early to late elderly, both sexes showed decreased functional capacity at a similar rate. ConclusionFunctional deterioration occurs to a similar extent in both sexes from early to late elderly. However, throughout the majority of the elderly period males demonstrate a greater muscle size, strength, and functional performance. Older females have greater MUFR variability and worse force steadiness than older males. These findings help to address the lack of MU data in older females, and suggest earlier interventions are needed in older females to prevent functional deterioration and reduce the health-sex paradox within ageing humans.

physiology↗

bioRxiv2021

Tensin3 interaction with talin drives formationof fibronectin-associated fibrillar adhesions

The formation of healthy tissue involves continuous remodelling of the extracellular matrix (ECM). Whilst it is known that this requires integrin-associated cell-ECM adhesion sites (CMAs) and actomyosin-mediated forces, the underlying mechanisms remain unclear. Here we examine how tensin3 contributes to formation of fibrillar adhesions (FBs) and fibronectin fibrillo-genesis. Using BioID mass spectrometry and a mitochondrial targeting assay, we establish that tensin3 associates with the mechanosensors talin and vinculin. We show that the talin R11 rod domain binds directly to a helical motif within the central intrinsically disordered region (IDR) of tensin3, whilst vinculin binds indirectly to tensin3 via talin. Using CRISPR knock-out cells in combination with defined tensin3 mutations, we show (i) that tensin3 is critical for formation of 5{beta}1-integrin FBs and for fibronectin fibrillogenesis, and (ii) the talin/tensin3 interaction drives this process, with vinculin acting to potentiate it.

cell biology↗

bioRxiv2021

Effects of High-Volume versus High-Load Resistance Training on Skeletal Muscle Growth and Molecular Adaptations

AimWe evaluated the effects of higher-load (HL) versus (lower-load) higher-volume (HV) resistance training on skeletal muscle hypertrophy, strength, and muscle-level molecular markers. MethodsTrained men (n=15, age: 23{+/-}3 y; training experience: 7{+/-}3 y) performed unilateral lower body training for 6 weeks (3x weekly), where single legs were assigned to HV and HL paradigms. Vastus lateralis (VL) biopsies were obtained prior to study initiation (PRE) as well as 3 days (POST) and 10 days following the last bout (POSTPR). Body composition and strength tests were performed at each testing session, and biochemical assays were performed on muscle tissue after study completion. Two-way within subjects repeated measures ANOVAs were performed on all dependent variables except tracer data, which was compared using dependent samples t-tests. ResultsA significant (p<0.05) interaction existed for unilateral leg extension 1RM (HV<HL at POST and POSTPR). Six-week integrated sarcoplasmic protein synthesis (iSarcoPS) rates were higher in the HV versus HL leg, while no difference between legs existed for integrated myofibrillar protein synthesis rates. Main time effects existed for unilateral leg press strength (PRE<POST and POSTPR), knee extensor peak torque (PRE and POST<POSTPR), dual-energy x-ray absorptiometry (DXA)-derived upper leg lean mass (PRE<POST and POSTPR), ultrasound-derived VL thickness (PRE and POSTPR<POST), sarcoplasmic protein concentrations (POST and POSTPR<PRE), and tropomyosin and troponin protein abundances (POST and POSTPR<PRE). ConclusionsWith the exception of differences in leg extensor strength and iSarcoPS between legs, our data suggest that short-term (6 weeks) HV and HL training elicit similar hypertrophic, strength, and molecular-level adaptations.

physiology↗

bioRxiv2019

Force-independent interactions of talin and vinculin govern integrin-mediated mechanotransduction

Talin, vinculin and paxillin are core components of the dynamic link between integrins and actomyosin. Here we study the mechanisms that mediate their activation and association using a mitochondrial-targeting assay, structure-based mutants, and advanced microscopy. As expected, full-length vinculin and talin are auto-inhibited and do not interact with each other in this state. Contrary to previous models that propose a critical role for forces driving talin-vinculin association, our data show that force-independent relief of auto-inhibition is sufficient to mediate their tight interaction. Interestingly, paxillin can bind to both talin and vinculin when either is inactive. Further experiments demonstrate that adhesions containing paxillin and vinculin can form without talin following integrin activation. However, these are largely deficient in exerting traction forces to the matrix. Our observations lead to a model whereby paxillin contributes to talin and vinculin recruitment into nascent adhesions. Activation of the talin-vinculin axis subsequently leads to the engagement with the traction force-machinery and focal adhesion maturation.

cell biology↗