Biology subjects

Cabrera, A. R.

Publications and source records attributed to Cabrera, A. R..

3 recordsLinked to original sources

bioRxiv2026

Exercise preconditioning confers skeletal muscle myometaplasticity

Previously exercise trained skeletal muscle is more growth-responsive to retraining. Using a murine training-detraining-retraining approach and multi-omics, we find that Pecam1 gene expression is lower, but capillarization is appreciably higher in previously trained (preconditioned) relative to naive trained control muscle. Greater capillarity could be permissive for accelerated hypertrophic adaptation. Exercise preconditioned myonuclei feature differential promoter CpG regulation in genes related to Wnt signaling. These epigenetic alterations with retraining align with our prior observations of methylation changes within the same pathway after a longer period of chronic training, suggesting a more rapid response due to preconditioning. Methylome-transcriptome integration and single myonucleus RNA-sequencing expose the polyamine metabolism enzyme Smox as a target that relates to heightened hypertrophic adaptability with retraining. Smox induction is sufficient to cause hypertrophy in aligned myotubes cultured on a stiffness-tuned substrate along with a growth-supportive transcriptional program. Integration of our multi-omics data suggests that Smox regulates repression of Ddit4/Redd1 (an inhibitor of mTORC1 signaling) after retraining. Smox may govern a favorable muscle fiber growth environment in previously trained muscle by sensitizing anabolic potential through polyamine metabolism. A lower adaptive threshold mediated by Smox could contribute to myometaplasticity, or a change to how subsequent muscle adaptations are made.

molecular biology↗

bioRxiv2025

The Age-Dependent Resident Myonuclear Multi-Omic Response to a Skeletal Muscle Hypertrophic Stimulus

A detailed analysis of how muscle fiber nuclei (myonuclei) respond to a hypertrophic stimulus would provide a critical step toward understanding compromised skeletal muscle plasticity with age. We used recombination-independent doxycycline-inducible myonucleus-specific fluorescent labelling, tissue RNA-sequencing, myonuclear DNA methylation analysis, multi-omic integration, and single myonucleus RNA-sequencing to define the molecular characteristics of adult (6-8 month) and aged (24 month) murine skeletal muscle after acute mechanical overload (MOV). In adult and aged MOV muscles, we found that: 1) similarities in the transcriptional response to loading - specifically in metabolism genes - were partly explained by a post-transcriptional microRNA-mediated mechanism, which we corroborated using an inducible muscle fiber-specific miR-1 knockout model, 2) differences in age-dependent transcriptional responses were linked to the magnitude and location of differential DNA methylation in resident myonuclei, specifically around hypertrophy-associated genes such as Myc, Runx1, Mybph, Ankrd1, collagen genes, and minichromosome maintenance genes, 3) adult and aged resident myonuclear transcriptomes had differing enrichment for innervation-related transcripts as well as unique transcriptional profiles in an Atf3+ "sarcomere assembly" population after MOV, and 4) cellular deconvolution analysis supports a role for neuromuscular junction regulation in age-specific hypertrophic adaptation. These data are a roadmap for uncovering molecular targets to enhance aged muscle adaptability.

cell biology↗

bioRxiv2022

The Time-Course of Cancer Cachexia Onset Reveals Biphasic Transcriptional Disruptions in Female Skeletal Muscle Distinct from Males

BackgroundCancer-cachexia (CC) is experienced by 80% of cancer patients, representing 40% of cancer-related deaths. Evidence suggests biological sex dimorphism is associated with CC. Assessments of the female transcriptome in CC are lacking and direct comparisons between biological sex are scarce. The purpose of this study was to define the time course of LLC-induced CC in females using transcriptomics, while directly comparing the effects of biological sex. MethodsEight-week-old female mice were injected with LLC cells (1x106) or sterile PBS to the hind flank. Tumors developed for 1, 2, 3 or 4-weeks. Due to dimorphism between tumor weight in 3- and 4-weeks of development, these were reorganized as low-tumor weight (LT, tumor-weight [≤]1.2g), or high-tumor weight (HT, tumor-weight [≥]2g). Gastrocnemius muscle was collected for RNA-sequencing (RNA-seq). Differentially expressed genes (DEGs) were defined as FDR<0.05. Data were further compared to RNA-seq of male mice from a previous study. ResultsGlobal gene expression of female gastrocnemius muscle reveals consistent DEGs at all timepoints, all associated with type-II interferon signaling (FDR<0.05). Early transcriptomic upregulation of extracellular-matrix pathways was noted at 1wk (p<0.05), JAK-STAT pathway was upregulated in 2wk, LT, and HT. Type II interferon signaling was downregulated in 1wk, LT, and HT (p<0.05). A second major transcriptomic downregulation in oxidative phosphorylation, electron transport chain and TCA cycle were noted in cachectic (HT) muscle only (p<0.05). Male-female comparison of cachectic groups revealed 69% of DEGs were distinct between sex (FDR<0.05). Comparison of the top 10-up and down DEGs revealed downregulation of type-II Interferon genes was unique to female, while males show upregulation of interferon-signaling pathways. ConclusionWe demonstrate biphasic disruptions in transcriptome of female LLC tumor-bearing mice: an early phase associated with ECM remodeling and a late phase, accompanied by onset of systemic cachexia, affecting overall skeletal muscle energy metabolism. Comparison of cachectic female-male mice reveals ~2/3 of DEGs are biological sex specific, providing evidence of dimorphic mechanisms of cachexia between sexes. Alterations to Type-II Interferon signaling appears specific to CC development in females, suggesting a new biological sex-specific marker of CC. Our data support biological sex dimorphisms in development of CC. HighlightsO_LIWhile males show impairments in skeletal muscle energy metabolism in early stages of CC, early transcriptomic alterations impact ECM remodeling that precedes impairments in skeletal muscle energy metabolism in female tumor-bearing mice. C_LIO_LI2/3 of differently expressed genes in skeletal muscle undergoing cachexia are biological sex specific. C_LIO_LIDownregulation of Type-II Interferon genes is unique to female mice, which displayed preserved gastrocnemius mass despite systemic cachexia, representing a potential therapeutic target for muscle mass maintenance in cancer-induced atrophy. C_LIO_LIMechanisms of LLC-induced cachexia appear to be biological sex specific which needs to be considered in further study of mechanisms and therapeutic modalities. C_LI

bioinformatics↗