Biology subjects

Pietrangelo, L.

Publications and source records attributed to Pietrangelo, L..

4 recordsLinked to original sources

bioRxiv2023

Voluntary wheel running mitigates disease in an Orai1 gain-of-function mouse model of tubular aggregate myopathy

Tubular aggregate myopathy (TAM) is an inherited skeletal muscle disease associated with progressive muscle weakness, cramps, and myalgia. Tubular aggregates (TAs) are regular arrays of highly ordered and densely packed SR straight-tubes in muscle biopsies; the extensive presence of TAs represent a key histopathological hallmark of this disease in TAM patients. TAM is caused by gain-of-function mutations in proteins that coordinate store-operated Ca2+ entry (SOCE): STIM1 Ca2+ sensor proteins in the sarcoplasmic reticulum (SR) and Ca2+-permeable ORAI1 channels in the surface membrane. We have previously shown that voluntary wheel running (VWR) prevents formation of TAs in aging mice. Here, we assessed the therapeutic potential of endurance exercise (in the form of VWR) in mitigating the functional and structural alterations in a knock-in mouse model of TAM (Orai1G100S/+ or GS mice) based on a gain-of-function mutation in the ORAI1 pore. WT and GS mice were singly-housed for six months (from two to eight months of age) with either free-spinning or locked low profile wheels. Six months of VWR exercise significantly increased soleus peak tetanic specific force production, normalized FDB fiber Ca2+ store content, and markedly reduced TAs in EDL muscle from GS mice. Six months of VWR exercise normalized the expression of mitochondrial proteins found to be altered in soleus muscle of sedentary GS mice in conjunction with a signature of increased protein translation and biosynthetic processes. Parallel proteomic analyses of EDL muscles from sedentary WT and GS mice revealed changes in a tight network of pathways involved in formation of supramolecular complexes, which were also normalized following six months of VWR. In summary, sustained voluntary endurance exercise improved slow twitch muscle function, reduced the presence of TAs in fast twitch muscle, and normalized the muscle proteome of GS mice consistent with protective adaptions in proteostasis, mitochondrial structure/function, and formation of supramolecular complexes.

physiology↗

bioRxiv2021

IDENTIFYING PLANT GENES SHAPING MICROBIOTA COMPOSITION IN THE BARLEY RHIZOSPHERE

A prerequisite to exploiting soil microbes for sustainable crop production is the identification of the plant genes shaping microbiota composition in the rhizosphere, the interface between roots and soil. Here we use metagenomics information as an external quantitative phenotype to map the host genetic determinants of the rhizosphere microbiota in wild and domesticated genotypes of barley, the fourth most cultivated cereal globally. We identify a small number of loci with a major effect on the composition of rhizosphere communities. One of those, designated the QRMC-3HS, emerges as a major determinant of microbiota composition. We subject soil-grown sibling lines harbouring contrasting alleles at QRMC-3HS and hosting contrasting microbiotas to comparative root RNA-seq profiling. This allows us to identify three primary candidate genes, including a Nucleotide-Binding-Leucine-Rich-Repeat (NLR) gene in a region of structural variation of the barley genome. Our results provide insights into the footprint of crop improvement on the plants capacity of shaping rhizosphere microbes.

plant biology↗

bioRxiv2021

Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors

To date there are no therapies for patients with congenital myopathies, muscle disorders causing poor quality of life of affected individuals. In approximately 30% of the cases, patients with congenital myopathies carry either dominant or recessive mutations in the RYR1 gene; recessive RYR1 mutations are accompanied by reduction of RyR1 expression and content in skeletal muscles and are associated with fiber hypotrophy and muscle weakness. Importantly, muscles of patients with recessive RYR1 mutations exhibit increased content of class II histone de-acetylases and of DNA genomic methylation. We recently created a mouse model knocked-in for the p.Q1970fsX16+p.A4329D RyR1 mutations, which are isogenic to those carried by a severely affected child suffering from a recessive form of RyR1-related multi-mini core disease. The phenotype of the RyR1 mutant mice recapitulates many aspects of the clinical picture of patients carrying recessive RYR1 mutations. We treated the compound heterozygous mice with a combination of two drugs targeting DNA methylases and class II histone de-acetylases. Here we show that treatment of the mutant mice with drugs targeting epigenetic enzymes improves muscle strength, RyR1 protein content and muscle ultrastructure. This study provides proof of concept for the pharmacological treatment of patients with congenital myopathies linked to recessive RYR1 mutations.

physiology↗

bioRxiv2019

Nitrogen Availability Modulates the Host Control of the Barley Rhizosphere Microbiota.

The microbiota populating the rhizosphere, the interface between roots and soil, can modulate plant growth, development and health. These microbial communities are not stochastically assembled from the surrounding soil but their composition and putative function are controlled, at least partially, by the host plant. Here we use the staple cereal barley as a model to gain novel insights into the impact of differential applications of nitrogen, a rate-limiting step for global crop production, on the host genetic control of the rhizosphere microbiota. Using a high-throughput amplicon sequencing survey, we determined that nitrogen availability for plant uptake is a factor promoting the selective enrichment of individual taxa in the rhizosphere of wild and domesticated barley genotypes. Shotgun sequencing and metagenome-assembled genomes revealed that this taxonomic diversification is mirrored by a functional specialisation, manifested by the differential enrichment of multiple GO-terms, of the microbiota of plants exposed to nitrogen conditions limiting barley growth. Finally, a plant soil feedback experiment revealed that the host control on the barley microbiota underpins the assembly of a phylogenetically diverse group of bacteria putatively required to sustain plant performance under nitrogen-limiting supplies. Taken together, our observations indicate that under nitrogen conditions limiting plant growth, plant-microbe and microbe-microbe interactions fine-tune the host genetic selection of the barley microbiota at both taxonomic and functional levels. The disruption of these recruitment cues negatively impacts plant growth. ImportanceThe microbiota inhabiting the rhizosphere, the thin layer of soil surrounding plant roots, can promote the growth, development, and health of their host plants. Previous research indicated that differences in the genetic composition of the host plant coincide with differences in the composition of the rhizosphere microbiota. This is particularly evident when looking at the microbiota associated to input-demanding modern cultivated varieties and their wild relatives, which have evolved under marginal conditions. However, the functional significance of these differences remains to be fully elucidated. We investigated the rhizosphere microbiota of wild and cultivated genotypes of the global crop barley and determined that nutrient conditions limiting plant growth amplify the host control on microbes at the root-soil interface. This is reflected in a plant- and genotype-dependent functional specialisation of the rhizosphere microbiota which appears required for optimal plant growth. These findings provide novel insights into the significance of the rhizosphere microbiota for plant growth and sustainable agriculture

plant biology↗