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Mechanotherapy promotes extracellular matrix remodeling in aged rat muscle recovering from disuse by reprogramming intercellular communication

ABSTRACT: Mechanotherapy promotes extracellular matrix remodeling in aged rat muscle recovering from disuse by reprogramming intercellular communication

PROVIDER: PRJNA764541 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15967539_1.fastq.gz	Fastqsanger.gz
	SRR15967539_2.fastq.gz	Fastqsanger.gz
	SRR15967540_1.fastq.gz	Fastqsanger.gz
	SRR15967540_2.fastq.gz	Fastqsanger.gz
	SRR15967541_1.fastq.gz	Fastqsanger.gz

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Mechanotherapy promotes extracellular matrix remodeling in aged rat muscle recovering from disuse by reprogramming intercellular communication

Project description:A mechanistic understanding of the age-related impairment to skeletal muscle regrowth following disuse atrophy as well as therapies to augment recovery in the aged are currently lacking. Mechanotherapy in the form of cyclic compressive loading has been shown to benefit skeletal muscle under a variety of paradigms, but not during the recovery from disuse in aged muscle. To determine whether mechanotherapy promotes extracellular matrix (ECM) remodeling, a critical aspect of muscle recovery after atrophy, we performed single cell RNA sequencing (scRNA-seq) of gastrocnemius muscle cell populations, stable isotope tracing of intramuscular collagen, and histology of the ECM in adult and aged rats recovering from disuse, with and without mechanotherapy. ECM remodeling-related gene expression in fibro-adipose progenitor cells (FAPs) was absent in aged compared to adult muscle following 7 days of recovery, and instead were enriched in chemoattractant genes. There was a significantly lower expression of genes related to phagocytic activity in aged macrophages during recovery, despite enriched chemokine gene expression of numerous stromal cell populations, including FAPs and endothelial cells. Mechanotherapy reprogrammed the transcriptomes of both FAPs and macrophages in aged muscle recovering from disuse to restore ECM-and phagocytosis-related gene expression, respectively. Stable isotope labeling of intramuscular collagen and histological evaluation confirmed mechanotherapy-mediated remodeling of the ECM in aged muscle recovering from disuse. In summary, our results highlight mechanisms underlying age-related impairments during the recovery from disuse atrophy and promote mechanotherapy as an intervention that reprograms the muscle transcriptional environment more similar to that of adult skeletal muscle.

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Project description:In the social amoebae (Dictyostelia) quorum sensing system mediates aggregation of single cells into multicellular aggregates by chemotactic movement towards gradients of diffusible molecules known as acrasins. The acrasin of P. violaceum is the unusual dipeptide N-propionyl-gamma-L-glutamyl-L-ornithine-delta-lactam-ethylester, known as glorin. Phylogenetic analysis has indicated that P. violaceum is more related to the most derived group 4 dictyostelids than to the ancient group 2 polysphondylids such as P. pallidum. Nevertheless it has been reported that P. pallidum cells respond to glorin in chemotaxis assays. This has led to the assumption that glorin-based communication may be the most ancient form of intercellular communication that Dictyostelia invented to organize early steps of multicellular development. In this study we show that glorin mediates rapid changes in gene expression at the transition from vegetative growth to aggregation, apparently without pronounced cross-talk with the cyclic AMP-based communication system that coordinates post-aggregation events in this species. We describe glorin-mediated changes in gene expression in the social amoeba Polysphondylium pallidum at the transition from unicellular growth to multicellular development. Comparison of gene expression in growing cells versus cells starving for 2 or 3 hours in the presence or absence of glorin.

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Delivery of a tissue derived extracellular matrix gel improves recovery following both acute and chronic disuse muscle injuries.

Project description:To evaluate decellularized skeletal muscle extracellular matrix hydrogel effectiveness in treating disuse atrophy using a mouse hindlimb suspension (HU) model. Male C57BL/6J mice were subjected to 5 days of hind limb unloading then received intramuscular matrix gel on the left TA. We then performed gene expression profiling analysis using data obtained from RNA-seq from mouse TA muscles (n=4 for matrix gel treatment, n=4 for PBS control , and n=4 for uninjured control) at day 7 post matrix gel injection

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