Abstract
Due to its similarity to humans, the pig is increasingly being considered as a good animal model for studying a range of human diseases. Despite their physiological similarities, differential expression of the myosin heavy chain (MyHC) IIB gene (MYH4) exists in the skeletal muscles of these species, which is associated with a different muscle phenotype. The expression of different MyHC isoforms is a critical determinant of the contractile and metabolic characteristics of the muscle fibre. We aimed to elucidate whether a genomic mechanism was responsible for the drastically different expression of MYH4 between pigs and humans, thus improving our understanding of the pig as a model for human skeletal muscle research. We utilized approximately 1 kb of the MYH4 promoter from a domestic pig and a human (which do and do not express MYH4, respectively) to elucidate the role of the promoter sequence in regulating the high expression of MYH4 in porcine skeletal muscle. We identified a 3 bp genomic difference within the proximal CArG and E-box region of the MYH4 promoter of pigs and humans that dictates the differential activity of these promoters during myogenesis. Subtle species-specific genomic differences within the CArG-box region caused differential protein-DNA interactions at this site and is likely accountable for the differential MYH4 promoter activity between pigs and humans. We propose that the genomic differences identified herein explain the differential activity of the MYH4 promoter of pigs and humans, which may contribute to the differential expression patterns displayed in these otherwise physiologically similar mammals. Further, we report that both the pig and human MYH4 promoters can be induced by MyoD over-expression, but the capacity to activate the MYH4 promoter is largely influenced by the 3 bp difference located within the CArG-box region of the proximal MYH4 promoter.
Highlights
Skeletal muscle is composed of a heterogeneous population of muscle fibres that display a broad spectrum of contractile and metabolic characteristics
Following transfection into mouse C2C12 muscle cells, activity of the 1 kb pig and human MYH4 promoters was restricted to differentiated myotubes, unlike a CMV-driven ZsGreen control, which was expressed in myoblasts and myotubes; see Figure 1A)
Both the pig and human MYH4 promoters were induced by a myogenic signal (MyoD), the absolute capacity for induction of the human MYH4 promoter was significantly restricted in comparison to the pig MYH4 promoter activity
Summary
Skeletal muscle is composed of a heterogeneous population of muscle fibres that display a broad spectrum of contractile and metabolic characteristics. Maximal shortening velocity of a muscle fibre is dictated by the predominant Myosin Heavy Chain (MyHC) isoform expressed [2] and increases in the order of MyHC I,IIA,IIX,IIB. Domesticated pigs remain an anomaly amongst the large mammals as they express high levels of MYH4 [22, 23], a phenotype likely exacerbated by the intensive selection pressure for enhanced muscle growth in these animals [24, 25]. This expression of MYH4 in pig skeletal muscle is associated with a dramatically faster and more glycolytic muscle phenotype compared to that of human skeletal muscle. Given the impact of MyHC isoform expression on the contractile and metabolic characteristics of the muscle fibre, it is interesting to explore the mechanisms dictating this unusually high expression of MYH4 in pig skeletal muscle, which currently remains unknown
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