Biology subjects

Sahinyan, K.

Publications and source records attributed to Sahinyan, K..

6 recordsLinked to original sources

bioRxiv2026

A Multiomic Analysis of Cachectic Mice Reveals Cancer Driven Suppression of Muscle Stem Cell Differentiation

Cancer cachexia affects a large proportion of cancer patients, inducing a rapid decline in muscle mass. Patients with cachexia have a worse prognosis and are less responsive to cancer therapies. The exact cause of cachexia remains unknown, nor are there any effective treatments for the condition. In this study, we use the C26 adenocarcinoma cell line to determine how cancer cells affect myofiber and muscle stem cell function. We determined that C26 cancer cells adapt to the host environment, in both male and female mice, greatly altering their transcriptome to promote their survival and growth. C26 cells directly communicate with muscle stem cells via GDF15 and MMP9. These circulatory factors cause the muscle stem cells to upregulate the EMT pathway and become less capable of undergoing differentiation and contributing to muscle regeneration. Muscle stem cells from tumor bearing mice are less proliferative and less prone to differentiation, Chromatin accessibility data shows that there are fewer accessible myogenic regulatory binding sites. Cytokine array determined that circulating GDF15 and MMP9 were highly upregulated and were derived form C26 tumor cells. However, blocking tumor derived GDF15 is not sufficient to prevent the onset of cachexia and rescue the loss of muscle stem cell function. Together, these findings establish a new conceptual paradigm in which cancer orchestrates muscle wasting through coordinated transcriptional, metabolic, and epigenetic suppression of muscle stem cell differentiation.

cell biology↗

bioRxiv2025

IRP1 deficiency alters mitochondrial metabolism and protects against metabolic syndrome pathologies

Iron regulatory protein 1 (IRP1) is a post-transcriptional regulator of cellular iron metabolism. In mice, loss of IRP1 causes polycythemia through translational de-repression of hypoxia-inducible factor 2 (HIF2) mRNA, which increases renal erythropoietin production. Here we show that Irp1-/- mice develop fasting hypoglycemia and are protected against high-fat diet-induced hyperglycemia and hepatic steatosis. Discovery-based proteomics of Irp1-/- livers revealed a mitochondrial dysfunction signature. Seahorse flux analysis in primary hepatocytes and differentiated skeletal muscle myotubes confirmed impaired respiratory capacity, with a shift from oxidative phosphorylation to glycolytic ATP production. This metabolic rewiring was associated with enhanced insulin sensitivity and increased glucose uptake in skeletal muscle. Under metabolic stress, IRP1 deficiency altered the redox balance of mitochondrial iron, resulting in inefficient energy production and accumulation of amino acids and metabolites in skeletal muscle, rendering them unavailable for hepatic gluconeogenesis. These findings identify IRP1 as a critical regulator of systemic energy homeostasis.

pathology↗

bioRxiv2023

The E3 Ubiquitin Ligase Nedd4L Acts as a Checkpoint Against Activation in Quiescent Muscle Stem Cells

Adult stem cells play a critical role in tissue repair and maintenance. In tissues with slow turnover, including skeletal muscle, these cells are maintained in a mitotically quiescent state yet remain poised to re-enter the cell cycle to replenish themselves and regenerate the tissue. Using a multiomics approach we identify the PAX7/NEDD4L axis as a checkpoint against muscle stem cell activation in homeostatic skeletal muscle. Our findings demonstrate that PAX7 transcriptionally activates the E3 ubiquitin ligase Nedd4L and that the conditional genetic deletion of Nedd4L impairs muscle stem cell quiescence, with an upregulation of cell cycle and myogenic differentiation genes. Loss of Nedd4L in muscle stem cells results in the expression of DCX which is only expressed during their in vivo activation. Together, this data establishes that the ubiquitin proteasome system, mediated by Nedd4L, is a key regulator of the muscle stem cell quiescent state in non-injured skeletal muscle. Highlights- General inhibition of the ubiquitin proteasome system with MG132 results in muscle stem cells (MuSCs) breaking quiescence. - The E3 ubiquitin ligase Nedd4L is a transcriptional target of Pax7. - The Pax7/Nedd4l axis restricts MuSC activation in homeostatic skeletal muscle. - Genetic deletion of Nedd4L induces MuSCs transition towards activation.

cell biology↗

bioRxiv2021

Application of ATAC-Seq for genome-wide analysis of the chromatin state at single myofiber resolution

Skeletal myofibers are the main components of skeletal muscle which is the largest tissue in the body. Myofibers are highly adaptive in nature and they can vary in different biological and disease conditions. Therefore, transcriptional and epigenetic studies on myofibers are crucial to discover how chromatin alterations occur in the skeletal muscle under different conditions. However, due to the heterogenous nature of skeletal muscle, studying myofibers in isolation proves to be a challenging task. Single cell sequencing has permitted for the study of the epigenome of isolated myonuclei. While this provides sequencing with high dimensionality, the sequencing depth is lacking, which makes comparisons between different biological conditions difficult. Here we report the first implementation of single myofiber ATAC-Seq, which permits for the sequencing of an individual myofiber at a depth sufficient for peak calling and for comparative analysis of chromatin accessibility under various physiological, physical and disease conditions. Application of this technique revealed significant differences in chromatin accessibility between resting and regenerating myofibers. This technique can lead to wide application in identifying chromatin regulatory elements and epigenetic mechanisms in muscle fibers during development and in muscle-wasting diseases.

genetics↗

bioRxiv2021

Transcriptional Reprogramming of Skeletal Muscle Stem Cells by the Niche Environment

Adult stem cells are indispensable for tissue regeneration. Tissue-specific stem cells reside in a specialized location called their niche, where they are in constant cross talk with neighboring niche cells and circulatory signals from their environment. Aging has a detrimental effect on the number and the regenerative function of various stem cells. However, whether the loss of stem cell function is a cause or consequence of their aging niche is unclear. Using skeletal muscle stem cells (MuSCs) as a model, we decouple cell-intrinsic from niche-mediated extrinsic effects of aging on their transcriptome. By combining in vivo MuSC heterochronic transplantation models and computational methods, we show that on a genome-wide scale, age-related altered genes fall into two distinct categories regarding their response to the niche environment. Genes that are inelastic in their response to the niche exhibit altered chromatin accessibility and are associated with differentially methylated regions (DMRs) between young and aged cells. On the other hand, genes that are restorable by niche exposure exhibit altered transcriptome but show no change in chromatin accessibility or DMRs. Taken together, our data suggest that the niche environment plays a decisive role in controlling the transcriptional activity of MuSCs, and exposure to a young niche can reverse approximately half of all age-associated changes that are not epigenetically encoded. The muscle niche therefore serves as an important therapeutic venue to mitigate the negative consequence of aging on tissue regeneration.

genetics↗

bioRxiv2019

Myf6/MRF4 is a Myogenic Niche Regulator Required for the Maintenance of the Muscle Stem Cell Pool

In metazoans, skeletal muscle evolved to contract and produce force. However, recent experimental evidence suggests that skeletal muscle has also acquired endocrine functions and produces a vast array of myokines. Using ChIP-Seq and gene expression analyses of myogenic factors, we show that Myf6/MRF4 transcriptionally regulates a broad spectrum of myokines and muscle-secreted proteins, including ligands for downstream activation of key signaling pathways such as EGFR, STAT3 and VEGFR. Homozygous deletion of Myf6 causes a significant reduction in the ability of muscle to produce key myokines such as EGF, VEGFA and LIF. Consequently, although Myf6 knockout mice are born with a normal muscle stem cell compartment, they undergo progressive reduction in their stem cell pool during postnatal life. Mechanistically, muscle stem cells from the Myf6 knockout animals show defects in activation of EGFR and STAT3 signaling, upregulate the p38 MAP kinase pathway and spontaneously break from quiescence. Exogenous application of recombinant EGF and LIF rescue the defects in the muscle stem cell pool of Myf6 knockout animals. Finally, skeletal muscles of mice lacking Myf6 have a significantly reduced ability to sustain donor-engrafted muscle stem cells. Taken together, our data uncovers a novel role for Myf6 in regulating the expression of niche factors and myokines to maintain the skeletal muscle stem cell pool in adult mice.

genetics↗