Gene expression changes controlling distinct adaptations in the heart and skeletal muscle of a hibernating mammal

Abstract

Throughout the hibernation season, the thirteen-lined ground squirrel ( Ictidomys tridecemlineatus) experiences extreme fluctuations in heart rate, metabolism, oxygen consumption, and body temperature, along with prolonged fasting and immobility. These conditions necessitate different functional requirements for the heart, which maintains contractile function throughout hibernation, and the skeletal muscle, which remains largely inactive. The adaptations used to maintain these contractile organs under such variable conditions serves as a natural model to study a variety of medically relevant conditions including heart failure and disuse atrophy. To better understand how two different muscle tissues maintain function throughout the extreme fluctuations of hibernation we performed Illumina HiSeq 2000 sequencing of cDNAs to compare the transcriptome of heart and skeletal muscle across the circannual cycle. This analysis resulted in the identification of 1,076 and 1,466 differentially expressed genes in heart and skeletal muscle, respectively. In both heart and skeletal muscle we identified a distinct cold-tolerant mechanism utilizing peroxisomal metabolism to make use of elevated levels of unsaturated depot fats. The skeletal muscle transcriptome also shows an early increase in oxidative capacity necessary for the altered fuel utilization and increased oxygen demand of shivering. Expression of the fetal gene expression profile is used to maintain cardiac tissue, either through increasing myocyte size or proliferation of resident cardiomyocytes, while skeletal muscle function and mass are protected through transcriptional regulation of pathways involved in protein turnover. This study provides insight into how two functionally distinct muscles maintain function under the extreme conditions of mammalian hibernation.

Prevention of muscle wasting and osteoporosis: the value of examining novel animal models

“…In another study on hibernating squirrels, a significant reduction in myostatin gene expression was found in soleus and diaphragm muscles, which are both resistant to atrophy in this species (Nowell et al, 2011). Other studies have shown reduced levels of myostatin mRNA during hibernation and aestivation, which could be associated with enhanced protein synthesis by facilitating mTOR signalling (Reilly et al, 2013;Vermillion et al, 2015).…”

“…Despite the need for global suppression of energetically expensive processes such as transcription and translation during dormancy (Storey and Storey, 2010), a number of recent studies have emphasised the importance of maintaining protein synthesis in hibernating muscle through activation of the mTOR signalling cascade (Andres-Mateos et al, 2013;Fedorov et al, 2014;Lee et al, 2010;Nowell et al, 2011). For example, hibernating I. tridecemlineatus were recently shown to exhibit increased expression of genes in the IGF1-AktmTOR signalling pathway (igf1, igf2, akt1, mTOR and rps6kb1), which is associated with the hypertrophic response to increased mechanical loading and is a key pathway promoting protein synthesis (Vermillion et al, 2015). Interestingly, genes encoding IGF-binding proteins, which have known functions in inhibiting protein synthesis, have also been reported to be strongly suppressed in the skeletal muscle of hibernating squirrels and aestivating frogs (Reilly et al, 2013;Vermillion et al, 2015).…”

“…For example, hibernating I. tridecemlineatus were recently shown to exhibit increased expression of genes in the IGF1-AktmTOR signalling pathway (igf1, igf2, akt1, mTOR and rps6kb1), which is associated with the hypertrophic response to increased mechanical loading and is a key pathway promoting protein synthesis (Vermillion et al, 2015). Interestingly, genes encoding IGF-binding proteins, which have known functions in inhibiting protein synthesis, have also been reported to be strongly suppressed in the skeletal muscle of hibernating squirrels and aestivating frogs (Reilly et al, 2013;Vermillion et al, 2015).…”

Nature's fat-burning machine: brown adipose tissue in a hibernating mammal

“…Moreover, BAT microRNAs were assessed during torpor in thirteen-lined ground squirrels and those with altered expression were linked to β-oxidation (Wu et al, 2014). Recently, BAT mRNA stability was investigated across the torpor-arousal cycle in thirteen-lined ground squirrels and revealed , cortex and hypothalamus regions of the brain , bone marrow (Cooper et al, 2016), and heart and skeletal muscle (Vermillion et al, 2015a). Measurements shown on the y-axis are means±s.e.m.…”

“…It is now possible to analyze the relatedness of the BAT transcriptome with transcriptomes from skeletal muscle (Hampton et al, 2011;Vermillion et al, 2015a) over the course of the hibernation season. Functionally, at the mitochondrial level, skeletal muscle and BAT behave similarly during hibernation (McFarlane et al, 2017; as reviewed by Staples, 2016).…”