Biology subjects

Chapple, P.

Publications and source records attributed to Chapple, P..

3 recordsLinked to original sources

bioRxiv2025

Chaperone AIP Couples mTORC1 Activation and Catabolic Metabolism During Neonatal Development

To grow and divide cells must tightly coordinate anabolic programs with the availability of nutrients and growth factors. This balance is especially critical during postnatal development, when biosynthetic and energetic demands are high, and nutrient supply and neonates have to adapt to periods of fasting. These conditions place acute stress on the proteostasis network, making autophagy essential for nutrient recycling. We found that the chaperone aryl hydrocarbon receptor-interacting protein (AIP) supports both arms of this metabolic balance: promoting anabolic PI3K-AKT signaling for mTORC1 activation and enabling catabolic processes such as proteasomal degradation and autophagy. Loss of AIP causes a severe neonatal metabolic disorder, where affected infants fail to thrive postnatally. Our findings establish AIP as a central regulator of neonatal metabolic adaptation and cellular homeostasis. One Sentence SummaryAIP integrates nutrient sensing and protein recycling to sustain neonatal survival.

developmental biology↗

bioRxiv2024

Network-based modelling reveals cell-type enriched patterns of non-coding RNA regulation during human skeletal muscle remodelling

A majority of human genes produce non-protein-coding RNA (ncRNA), and some have roles in development and disease. Neither ncRNA nor human skeletal muscle is ideally studied using short-read sequencing, so we used a customised RNA pipeline and network modelling to study cell-type specific ncRNA responses during muscle growth at scale. We completed five human resistance-training studies (n=144 subjects), identifying 61% who successfully accrued muscle-mass. We produced 288 transcriptome-wide profiles and found 110 ncRNAs linked to muscle growth in vivo, while a transcriptome-driven network model demonstrated interactions via a number of discrete functional pathways and single-cell types. This analysis included established hypertrophy-related ncRNAs, including CYTOR - which was leukocyte-associated (FDR = 4.9 x10-7). Novel hypertrophy-linked ncRNAs included PPP1CB-DT (myofibril assembly genes, FDR = 8.15 x 10-8), and EEF1A1P24 and TMSB4XP8 (vascular remodelling and angiogenesis genes, FDR = 2.77 x 10-5). We also discovered that hypertrophy lncRNA MYREM shows a specific myonuclear expression pattern in vivo. Our multi-layered analyses established that single-cell-associated ncRNA are identifiable from bulk muscle transcriptomic data and that hypertrophy-linked ncRNA genes mediate their association with muscle growth via multiple cell types and a set of interacting pathways. One Sentence SummaryWe used an optimised transcriptomic strategy to identify a set of ncRNA genes regulated during skeletal muscle hypertrophy in one hundred and forty-four people, with network modelling and spatial imaging providing biological context.

bioinformatics↗

bioRxiv2024

Biallelic Loss of Molecular Chaperone Molecule AIP Results in a Novel Severe Multisystem Disease Defined by Defective Proteostasis

Children born with deleterious biallelic variants of the chaperone aryl hydrocarbon receptor interacting protein (AIP) have a novel pediatric metabolic disease presenting a severe, complex clinical phenotype characterized by failure to develop following birth. Analysis of Aip knockout mouse embryonic fibroblasts and patient-derived dermal fibroblasts revealed that AIP was required to support proteostasis; including proteasome activity, induction of autophagy and lysosome function. aip knockout zebrafish, recapitulated the phenotype of the children; dying at an early stage of development when autophagy is required to adapt to periods of starvation. Our results demonstrate that AIP plays a crucial role in initiating autophagy and maintaining proteostasis in vitro and in vivo. One Sentence SummaryHomozygous loss of the chaperone AIP results in a novel pediatric disease exhibiting multiple features of a lysosomal storage disease.

molecular biology↗