Biology subjects

Battey, E.

Publications and source records attributed to Battey, E..

8 recordsLinked to original sources

bioRxiv2026

Plasma proteomics identifies an IL-6–associated SAA axis linked to muscle wasting in patients with cancer cachexia

Nearly half of patients with advanced lung cancer develop cachexia, a debilitating syndrome that worsens prognosis. We conducted longitudinal clinical and plasma proteomic profiling of 67 patients with non-small cell lung cancer, with and without cachexia, during first-line treatment. Patients with cachexia at diagnosis exhibited elevated risk of hospitalization and treatment-delaying toxicity. At diagnosis, 128 plasma proteins were upregulated and 67 downregulated in cachectic relative to non-cachectic patients. Longitudinal assessments of body composition, physical performance, metabolism, clinical outcomes, and nutritional risk revealed distinct fat and muscle wasting phenotype trajectories. 71 proteins were associated with fat loss, 92 with muscle loss, and 177 with concurrent muscle and weight loss. We identified and functionally validated 8 plasma proteins linked to muscle loss and adverse clinical outcomes. In a separate cohort of 147 patients with advanced pancreatic cancer receiving the interleukin-6 (IL-6) inhibitor tocilizumab, pharmacological suppression of serum amyloid A (SAA) levels following IL-6 inhibition suggests a systemic IL-6-SAA axis. These results collectively highlight SAA1 and SAA2 as IL-6-driven, cachexia-associated factors that reduce human myotube width. These findings uncover new potential therapeutic targets for cachexia.

Systems Biology↗

bioRxiv2025

Proteomic and phospho-proteomic longitudinal signatures of human skeletal muscle in lung cancer cachexia

Weight loss is a potentially deadly hallmark of many cancers, including lung cancer. In particular, the loss of skeletal muscle mass and function impairs survival and lowers quality of life. Despite being a major determinant of prognosis, the molecular drivers of muscle wasting remain ill-defined. Therefore, there is a critical need for human molecular data to support the development of effective therapies for this currently untreatable condition. Here, we utilize cutting-edge proteomics technology to longitudinally map the proteome and phosphoproteome of skeletal muscle from patients with newly diagnosed, advanced-stage non-small cell lung cancer during their treatment. Leveraging deep in vivo clinical phenotyping of activity, body composition, muscle quality, and nutritional risk, we identified 118/174 muscle proteins/phospho-sites associated with cachexia at diagnosis with indications of sexual dimorphism. Treatment altered 278 proteins and 1,155 phospho-sites, of which 137/91 proteins/phospho-sites were associated with muscle wasting. Our findings highlight disrupted calcium, anabolic, and stress signalling, alongside extracellular matrix and mitochondrial alterations, as key molecular features of cachexia in non-small cell lung cancer. These clinically anchored proteomic and phosphoproteomic signatures provide potential targets for future research.

molecular biology↗

bioRxiv2025

Pathophysiological remodeling of the skeletal muscle microenvironment in patients with lung cancer

Background Muscle wasting, systemic inflammation, and functional decline are highly prevalent and detrimental in patients with advanced-stage non small cell lung cancer (NSCLC). Methods: In this cross sectional study, we investigated NSCLC associated muscle remodeling by analyzing skeletal muscle biopsies from patients with NSCLC (n = 18) and matched controls (n = 18) using quantitative proteomics, histology, fluorescence-activated cell sorting, gene expression profiling, and high resolution respirometry. Findings: NSCLC muscle was characterized by type II muscle fiber atrophy, greater collagen deposition, and redistribution of lipids to the extracellular matrix (ECM), together with remodeling of the inflammatory, immune, ECM and mitochondrial proteome. Additionally, mitochondrial respiratory capacity and morphology were altered in patients with NSCLC, which was associated with increased oxidative stress and dysregulated calcium handling. Concomitantly, we detected STAT3 activation and immune cell alterations, which may negatively impact skeletal muscle health in patients with NSCLC. Finally, we identified a shift in fibro-adipogenic progenitors (FAPs), favoring the CD90 subtype. Mechanistically, conditioned media from patient-derived FAPs reduced myotube width in vitro, uncovering a novel mechanism by which altered paracrine signaling from the muscle resident stromal compartment drives atrophy in cancer cachexia. Interpretation: These findings provide human evidence that altered FAP composition, mitochondrial homeostasis, calcium handling, and immune cell landscape accompany muscle wasting in NSCLC, which may inform therapeutic strategies to preserve skeletal muscle health in patients with cancer.

molecular biology↗

bioRxiv2025

Activin receptor type IIA/B blockade increases muscle mass and strength, but compromises glycemic control in mice

Short abstractO_ST_ABSPurposeC_ST_ABSBlocking the Activin receptor type IIA and B (ActRIIA/IIB) has clinical potential to increase muscle mass and improve glycemic control in obesity, cancer, and aging. However, the impact of blocking ActRIIA/IIB on strength, metabolic regulation and insulin action remains unclear. MethodsHere, we investigated the effect of short- (10 mg/kg once, 40h) or long-term (10 mg/kg twice weekly, 21 days) antibody targeting ActRIIA/IIB (ActRIIA/IIBab) in lean and diet-induced obese mice and engineered human muscle tissue. ResultsShort-term ActRIIA/IIB administration in lean mice increased insulin-stimulated glucose uptake in skeletal muscle by 76-105%. Despite this, ActRIIA/IIB-treated mice exhibited 33% elevated fasting blood glucose and glucose intolerance. Moreover, long-term ActRIIA/IIB treatment increased average muscle mass (20%) and reduced fat mass (-8%) in obese mice but did not change insulin-stimulated glucose uptake in skeletal muscle or adipose tissue, yet induced marked glucose intolerance, and increased hepatic glucose output in response to pyruvate. Concomitantly, long-term ActRIIA/IIBab treatment increased strength (30%) in mouse soleus muscle and prevented activin A-induced loss of tissue strength in engineered human muscle tissue. Surprisingly, long-term ActRIIA/IIBab treatment lowered volitional running (-250%). ConclusionOur findings demonstrate that, in accordance with human studies, ActRIIA/IIB blockade holds promise for increasing muscle mass, strength, and insulin sensitivity. However, contrary to the improved glycemic control in humans, ActRIIA/IIB blockade in mice causes severe glucose intolerance and lowers voluntary physical activity. Our study underscores the complex metabolic and functional consequences of ActRIIA/IIB blockade, and highlight species differences on glycemic control, which warrant further investigation.

molecular biology↗

bioRxiv2024

Protocol for muscle fiber type and cross-sectional areaanalysis in cryosections of whole lower mouse hindlimbs

We outline a robust, simple, and cost-effective method to simultaneously visualize all mouse lower hindlimb skeletal muscles. We describe procedures for orientating the whole lower hindlimb in gum tragacanth prior to freezing, simplifying the proceeding experimental steps, and enhancing the clarity and comprehensiveness of characterizations. We then detail steps for quantifying muscle fiber size and fiber type characteristics in a single cryosection using immunofluorescence and histochemistry. This protocol can be applicable for commonly used histological and (immuno) histochemical evaluations such muscle degeneration/regeneration, fibrosis, immune cell infiltration, enzymatic activity and glycogen content. HighlightsO_LIEmbedding and orientating mouse lower hindlimb in tragacanth before freezing enhances clarity and simplifies steps. C_LIO_LISimultaneously visualizing myofibers in different muscle compartments enables efficient and comprehensive evaluations of morphology and physiological characteristics. C_LIO_LISingle cryosection analysis of myofiber size and types with immunofluorescence. C_LIO_LIApplicable for evaluating muscle degeneration, fibrosis, and immune infiltration. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/608909v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@9d3fe4org.highwire.dtl.DTLVardef@1cdcc85org.highwire.dtl.DTLVardef@2e494eorg.highwire.dtl.DTLVardef@cebfc6_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2023

Muscle fibre size and myonuclear positioning in trained and aged humans

Myonuclear domain (MND) is the theoretical volume of cytoplasm within which a myonucleus is responsible for transcribing DNA. Changes in myonuclear number, organisation, and myonuclear domain size are associated with exercise adaptations and ageing. However, data on satellite cell activation, changes in MND volumes and myonuclear arrangement following exercise are inconsistent. Additionally, whether MNDs and myonuclear arrangement are altered with age remains unclear. The aim of the present investigation was therefore to investigate relationships between age and activity status and myonuclear numbers and organisation. Muscle fibres from younger trained (YT) and older trained (OT) individuals were compared with age-matched untrained counterparts (YU and OU). Serial, optical z-slices were acquired throughout isolated muscle fibres and analysed to give 3D coordinates for myonuclei and muscle fibre dimensions, respectively. As expected, mean cross-sectional area (CSA) (m2) of muscle fibres from OU was 29-42% smaller compared to the other groups. Number of nuclei relative to fibre CSA was 87% greater in OU compared to YU muscle fibres (P < 0.05). Additionally, scaling of myonuclear domain volume with fibre size was altered in older untrained individuals. Myonuclear arrangement, on the other hand, was similar across groups. These data indicate that regular endurance exercise throughout the lifespan may preserve the size of single muscle fibres in older age and maintain the relationship between fibre size and MND volumes. Inactivity, however, may result in reduced muscle fibre size and disrupted relationship between fibre size and MND volumes. Plain Language SummaryIn this study, we examined the relationship between physical activity and the characteristics of muscle fibres in individuals of different age groups. We focused on a concept called the myonuclear domain (MND), which refers to the volume surrounding muscle nuclei or myonuclei that house the genome. We wanted to understand how changes in myonuclear number, organisation, and MND size were influenced by exercise and aging. To do this, we compared muscle fibres from younger trained individuals, older trained individuals, and age-matched untrained individuals. The results showed that the average size of muscle fibres in the untrained older individuals was smaller compared to the other groups. Moreover, the number of nuclei relative to fibre size was significantly higher in the untrained older individuals. However, myonuclear arrangement was similar across all groups. These findings suggest that regular endurance exercise throughout life may help maintain muscle fibre size, myonuclear numbers, MND volumes, and myonuclear organisation in older individuals. Conversely, inactivity can lead to reduced muscle fibre size and disrupted relationship between fibre size and MND volumes. These results have important implications for understanding the effects of exercise and aging on muscle health.

physiology↗

bioRxiv2022

Exercise induces myonuclear remodelling in humans independently of age

Age-related decline in skeletal muscle structure and function can be mitigated by regular exercise. However, the precise mechanisms that govern this are not fully understood. The nucleus plays an active role in translating forces into biochemical signals (mechanotransduction), with nuclear lamina protein Lamin A regulating nuclear shape, nuclear mechanics, and ultimately gene expression. Defective Lamin A expression causes muscle pathologies and premature ageing syndromes, but the roles of nuclear structure and function in physiological ageing and in exercise adaptations remain obscure. Here, we isolated single muscle fibres and carried out detailed morphological and functional analyses on myonuclei from young and older exercise-trained individuals. Strikingly, myonuclei from trained individuals were more spherical, less deformable, and contained a thicker nuclear lamina than untrained individuals. Complementary to this, exercise resulted in increased levels of Lamin A and increased myonuclear stiffness in mice. We conclude that exercise is associated with myonuclear remodelling, independently of age, which may contribute to the preservative effects of exercise on muscle function throughout the lifespan. Key pointsO_LIThe nucleus plays an active role in translating forces into biochemical signals C_LIO_LIMyonuclear aberrations in a group of muscular dystrophies called laminopathies suggest that the shape and mechanical properties of myonuclei are important for maintaining muscle function. C_LIO_LIHere, we present striking differences in myonuclear shape and mechanics associated with exercise, in both young and old humans. C_LIO_LIMyonuclei from trained individuals were more spherical, less deformable, and contained a thicker nuclear lamina than untrained individuals. C_LIO_LIWe conclude that exercise is associated with age-independent myonuclear remodelling, which may help to maintain muscle function throughout the lifespan. C_LI

cell biology↗

bioRxiv2022

Lem2 is essential for cardiac development by maintaining nuclear integrity

Nuclear envelope integrity is essential for compartmentalisation of nucleus and cytoplasm. Importantly, mutations in nuclear envelope-encoding genes are the second-highest cause of familial dilated cardiomyopathy. One such nuclear envelope protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in mechanically active tissue such as heart remains poorly understood. We generated mice in which Lem2 was specifically ablated in cardiomyocytes and carried out detailed physiological, tissue and cellular analyses. Importantly, our data showed that Lem2 was essential for cardiac development, and hearts from Lem2 cKO mice were morphologically and transcriptionally underdeveloped. Lem2 cKO hearts displayed high levels of DNA damage, nuclear rupture, and apoptosis. Crucially, we found that these defects were driven by muscle contraction as they were ameliorated by inhibiting myosin contraction and conversely were exacerbated upon myosin activation. Our data suggest that Lem2 is critical for integrity at the nascent nuclear envelope in fetal hearts, and protects the nucleus from the mechanical forces of muscle contraction. Taken together, these data provide novel insight into mechanisms underlying striated muscle diseases caused by altered nuclear envelope integrity.

cell biology↗