Abstract
Levels of myostatin expression and physical activity have both been associated with transcriptome dysregulation and skeletal muscle hypertrophy. The transcriptome of triceps brachii muscles from male C57/BL6 mice corresponding to two genotypes (wild-type and myostatin-reduced) under two conditions (high and low physical activity) was characterized using RNA-Seq. Synergistic and antagonistic interaction and ortholog modes of action of myostatin genotype and activity level on genes and gene pathways in this skeletal muscle were uncovered; 1,836, 238, and 399 genes exhibited significant (FDR-adjusted P-value < 0.005) activity-by-genotype interaction, genotype and activity effects, respectively. The most common differentially expressed profiles were (i) inactive myostatin-reduced relative to active and inactive wild-type, (ii) inactive myostatin-reduced and active wild-type, and (iii) inactive myostatin-reduced and inactive wild-type. Several remarkable genes and gene pathways were identified. The expression profile of nascent polypeptide-associated complex alpha subunit (Naca) supports a synergistic interaction between activity level and myostatin genotype, while Gremlin 2 (Grem2) displayed an antagonistic interaction. Comparison between activity levels revealed expression changes in genes encoding for structural proteins important for muscle function (including troponin, tropomyosin and myoglobin) and for fatty acid metabolism (some linked to diabetes and obesity, DNA-repair, stem cell renewal, and various forms of cancer). Conversely, comparison between genotype groups revealed changes in genes associated with G1-to-S-phase transition of the cell cycle of myoblasts and the expression of Grem2 proteins that modulate the cleavage of the myostatin propeptide. A number of myostatin-feedback regulated gene products that are primarily regulatory were uncovered, including microRNA impacting central functions and Piezo proteins that make cationic current-controlling mechanosensitive ion channels. These important findings extend hypotheses of myostatin and physical activity master regulation of genes and gene pathways, impacting medical practices and therapies associated with muscle atrophy in humans and companion animal species and genome-enabled selection practices applied to food-production animal species.
Highlights
Genetic and non-genetic conditions impact the molecular pathways and physiology of the skeletal muscle
Considering that myostatin inhibition and physical activity are being explored as treatment options for muscle degeneration and other disorders, it is important to understand the impact of these factors at the gene co-regulation level
Hypertrophic cardiomyopathy is characterized by an hypertrophied heart muscle while tricep samples were used in this study, our results suggest that the expression of genes in similar biological processes are altered by myostatin genotype regardless of activity level
Summary
Genetic and non-genetic conditions impact the molecular pathways and physiology of the skeletal muscle. Myostatin negatively regulates muscle fiber number during skeletal muscle development [1,2] and inhibits myogenic differentiation by reducing mRNA levels of the muscle regulatory factors [3,4]. Myostatin deficiency caused by alterations at the DNA or RNA level is linked to increased numbers and size of muscle fibers, a phenomenon often referred to as ‘double muscling [5]. Physical activity influences muscle fiber in manners akin to the effect of myostatin deficiency [7]. Muscle inflammation caused by physical activity is accompanied by an increase of nitric oxide (NO) production, and skeletal muscle derived NO regulates contraction and metabolism as well as modulates muscle glucose uptake during activity [11]
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