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Analysis of noncoding RNAs in human muscle and their regulation during muscle growth

ABSTRACT: A majority of genes code for non-protein-coding RNA (ncRNA). Only a handful of ncRNA have characterised molecular functions, including key epigenetic roles in development and human disease. In human skeletal muscle reliance on suboptimal sequencing-based data has obfuscated characterization of ncRNAs. Herein, using more comprehensive RNA profiling and data-driven quantitative network methods we study regulation of ncRNAs during skeletal muscle hypertrophy. Across five independent supervised exercise-training studies (n=144), 61% of individuals accrued muscle mass beyond established technical variation (lean mass responders, LMR) with the remainder show no measurable lean mass response (NMLMR). The LMR group alone demonstrated differential expression (DE) of 50 ncRNA genes (FDR <1%) and further modelling identified a total of 110 ncRNAs of potential interest. Critically, expression of these ncRNAs was indistinguishable between LMR vs NMLMR at baseline. Notably, <5% of these candidate ncRNAs were detected as being regulated by exercise training using sequencing. A robust co-expression model of the human muscle transcriptome (n=437) used to assign each ncRNA to functional pathways or single-cell types. Candidates, such as the hypertrophy-related ncRNA CYTOR, was leukocyte associated (FDR = 4.9 x10-7; FE = 6.6) and highly expressed in immune-related cells. PPP1CB-DT co-expressed with myofibril assembly genes (FDR = 8.2 x10-8; FE = 47.5), positively associating with type II fibre markers (e.g., TNNT3: r =0.37; FDR = 2.57 x10-14), while others (e.g. EEF1A1P24 and TMSB4XP8) co-expressed angiogenesis pathways. MYREM was positively associated with hypertrophy and we established it has a distinct myonuclear expression in vivo, using merfish probes. We show that single-cell type associations are readily identifiable from bulk transcriptomic data, and that hypertrophy-linked ncRNA genes appear to mediate their association with muscle growth via multiple cell types. A total of 144 paired sample comparisons were made for the continous (change in lean mass) versus change in gene expression analysis using 137 paris of samples. 7 baseline samples from the HALL study represent a single baseline biopsy and thereafter each leg was subject to a distinct RT protocol with an individual measure of lean mass before and lean mass afterwards from the same leg.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270823 | GEO | 2024/06/26

REPOSITORIES: GEO

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Project description:Muscle ring finger-1 (MuRF1) is a muscle-specific protein implicated in the regulation of cardiac myocyte size and contractility. MuRF2, a closely related family member, redundantly interacts with protein substrates, and hetero-dimerizes with MuRF1. Mice lacking either MuRF1 or MuRF2 are phenotypically normal whereas mice lacking both proteins develop a spontaneous cardiac and skeletal muscle hypertrophy indicating cooperative control of muscle mass by MuRF1 and MuRF2. In order to identify the role that MuRF1 plays in regulating cardiac hypertrophy in vivo, we created transgenic mice expressing increased amounts of cardiac MuRF1. Adult MuRF1 transgenic (Tg+) hearts exhibited a non-progressive thinning of the left ventricular wall and a concomitant decrease in cardiac function. Experimental induction of cardiac hypertrophy by trans-aortic constriction (TAC) induced rapid failure of MuRF1 Tg+ hearts. Microarray analysis identified that the levels of genes associated with metabolism (and in particular mitochondrial processes) were significantly altered in MuRF1 Tg+ hearts, both at baseline and during the development of cardiac hypertrophy. Surprisingly, ATP levels in MuRF1 Tg+ mice did not differ from wild type mice despite the depressed contractility following TAC. To explain this discrepancy between the ongoing heart failure and maintained ATP levels in MuRF1 Tg+ hearts, we compared the level and activity of creatine kinase (CK) between wild type and MuRF1 Tg+ hearts. Although mCK and CK-M/B protein levels were unaffected in MuRF1 Tg+ hearts, total CK activity was significantly inhibited. We conclude that MuRF1’s inhibition of CK activity leads to increased susceptibility to heart failure following TAC, demonstrating for the first time that MuRF1 regulates cardiac energetics in vivo. Keywords: Genetic modification, physiological manipulation. Three-condition experiment, MuRF1 Tg+ vs. WT mice. Biological replicates: 4 WT baseline, 3 MuRF1 Tg+ baseline, cardiac overpressure hypertrophy induced by trans-aortic banding at 1 week (3 WT, 3 MurF Tg) and 4 weeks (3 WT, 3 MurF Tg), hearts harvested. One replicate per array.

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Analysis of noncoding RNAs in human muscle and their regulation during muscle growth

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