Abstract
Skeletal muscle comprises a family of diverse tissues with highly specialized morphology, function, and metabolism. Many acquired diseases – including HIV, COPD, cancer cachexia, critical illness myopathy, and sepsis – affect specific muscles while sparing others. Even monogenic muscular dystrophies tend to selectively affect certain muscle groups, despite their causative genetic mutations being present in all tissues. These observations suggest that factors intrinsic to muscle tissues influence their susceptibility to various disease mechanisms. Nevertheless, most studies have not addressed transcriptional diversity among skeletal muscles. Here we use unbiased RNA sequencing (RNAseq) to profile global mRNA expression in a wide array of skeletal, smooth, and cardiac muscle tissues from mice and rats. Our data set, MuscleDB, reveals extensive transcriptional diversity, with greater than 50% of transcripts differentially expressed among skeletal muscle tissues. This diversity is only partly explained by fiber type composition and developmental history, suggesting that specialized transcriptional profiles establish the functional identity of muscle tissues. We find conservation in the transcriptional profiles across species as well as between males and females, indicating that these data may be useful in predicting gene expression in related species, such as humans. Notably, thousands of differentially expressed genes in skeletal muscle are associated with human disease, and hundreds of these genes encode targets of drugs on the market today. Related to this observation, we suggest a mechanistic explanation for how myotonic dystrophy induces weakness in the extensor digitorum longus (EDL) while sparing nearby muscles. These data may therefore provide the means by which muscle-specific sensitivity to disease may be unraveled. In addition, we detect hundreds of putative myokines that may underlie the endocrine functions of skeletal muscle. We anticipate that in conjunction with transcriptional modeling, this resource will catalyze more sophisticated tissue engineering of skeletal muscle to improve the efficacy of regenerative medicine.
Highlights
Gene expression atlases have made enormous contributions to our understanding of genetic regulatory mechanisms
We find that more than 50% of transcripts are differentially expressed among skeletal muscle tissues, an observation that cannot be explained by fiber type composition or developmental history alone
Functional genomics studies have acted on this assumption to the extent that every gene expression atlas generated to-date has selected at most one skeletal muscle as representative of the entire family of tissues
Summary
Gene expression atlases have made enormous contributions to our understanding of genetic regulatory mechanisms. The field of functional genomics was set in motion by the completion of the Human Genome Project and the coincident development of high throughput gene expression profiling technologies. The overriding goals of this field are to understand how genes and proteins interact at a whole-genome scale and to define how these interactions change across time, space, and different disease states. The development of SymAtlas was an early, influential effort to address these questions (Su et al, 2002). Custom microarrays were used to systematically profile mRNA expression in dozens of tissues and cell lines from humans and mice. Besides describing tissue-specific expression patterns, these data provided essential insights into the relationship between chromosomal structure and transcriptional regulation (Su et al, 2004)
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