Skeletal Muscle Gene Expression Profile in Response to Caloric Restriction and Aging: A Role for SirT1.

Matthew J Myers,Fathima Shaik,Junaith S Mohamed,Stephen E Alway,Fahema Shaik

doi:10.3390/genes12050691

Abstract

SirT1 plays a crucial role in the regulation of some of the caloric restriction (CR) responsive biological pathways. Aging suppresses SirT1 gene expression in skeletal muscle, suggesting that aging may affect the role of CR in muscle. To determine the role of SirT1 in the regulation of CR regulated pathways in skeletal muscle, we performed high-throughput RNA sequencing using total RNA isolated from the skeletal muscles of young and aged wild-type (WT), SirT1 knockout (SirT1-KO), and SirT1 overexpression (SirT1-OE) mice fed to 20 wk ad libitum (AL) or 40% CR diet. Our data show that aging repressed the global gene expression profile, which was restored by CR via upregulating transcriptional and translational process-related pathways. CR inhibits pathways linked to the extracellular matrix and cytoskeletal proteins regardless of aging. Mitochondrial function and muscle contraction-related pathways are upregulated in aged SirT1 KO mice following CR. SirT1 OE did not affect whole-body energy expenditure or augment skeletal muscle insulin sensitivity associated pathways, regardless of aging or diet. Overall, our RNA-seq data showed that SirT1 and CR have different functions and activation of SirT1 by its activator or exercise may enhance SirT1 activity that, along with CR, likely have a better functional role in aging muscle.

Highlights

Sir2, the mammalian homolog of SirT1 (Sirtuin 1), was originally identified in budding yeast, Saccharomyces cerevisiae, as a key regulator of lifespan [1,2]
We have previously shown that aging represses both SirT1 gene expression and activity in skeletal muscle [10]
No genes were differentially regulated at ≥2-fold. These results indicate that increased SirT1 activity in skeletal muscle altered a lesser number of genes, which are less than 2-fold

Summary

Introduction

Sir (silent information regulator 2), the mammalian homolog of SirT1 (Sirtuin 1), was originally identified in budding yeast, Saccharomyces cerevisiae, as a key regulator of lifespan [1,2]. Studies from other lower model organisms such as worms and flies proved the role of Sir homologs in governing lifespan [3]. All sirtuins are NAD+ -dependent protein deacetylases, which are involved in numerous pathophysiological roles such as aging, metabolism, cancer, skeletal muscle adaptation, inflammation, and neurodegeneration [4,5,6,7,8,9,10,11,12,13]. The most studied member of the mammalian sirtuin family is SirT1. SirT1 was originally identified as one of the deacetylases of histone proteins, SirT1 deacetylates many non-histone proteins

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