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  • With respect to the muscle compartment

    2020-07-02

    With respect to the muscle compartment, only low protein expression of ASB9 has been detected in healthy human skeletal muscle [as reported in the Human Protein Atlas (HPA)], whereas high levels of Asb5 protein expression are detected in mammalian skeletal muscle, which appears to be important in the recovery of muscle after exercise [29]. In this sense, Asb5 appears to have to taken over the function of asb9/11 in zebrafish. Accordingly, there is no Asb5 homolog in the zebrafish genome. Another compartment in which evidence has been obtained for a role of six-ankyrin repeat and SOCS box-containing proteins is the spermatogenic compartment. In mice, spermatocytes and spermatids express Asb9 but spermatogonia and generated spermatozoa do not; thus, Asb9 appears to be a specific marker of active spermatogenesis in mice [30]. Although expression of ASB9 and ASB11 is low in healthy human adult muscle, they are highly expressed in Pax7+ muscle satellite cells [31]. Pax7+ is thought to be a marker and regulator of the skeletal muscle stem cell population and to support muscle regeneration through Notch signaling [32], thus providing an obvious link to Asb genes and muscle compartment expansion. In apparent agreement, whereas expression of the terminal differentiation marker muscle-specific creatine kinase increases throughout somitogenesis, expression of is highest during early zebrafish myogenesis and diminishes during the final stages of muscle differentiation, which is similar to the pattern of creatine kinase expression. Overexpression of d-asb9/11 resulted in impaired terminal differentiation in the zebrafish skeletal muscle compartment and stimulated expansion of the muscle progenitor cell population. Conversely, a germline d-asb9/11 mutation in zebrafish caused precocious differentiation of muscle progenitors and impaired muscle cell regeneration after adult muscle cell injury. Hence, d-asb9/11 is a regulator of myogenesis and embryonic muscle development in zebrafish [18]. Asb5 may also be linked to the size of the vascular compartment. At the beginning of arteriogenesis, Asb5 is highly expressed in rabbit endothelial and smooth muscle cells of src inhibitor and veins and also during expansion of the vasculature; for example, during collateral artery generation, both Asb5 mRNA and protein levels are significantly upregulated [33]. Intriguingly, in humans, circulating levels of six-ankyrin repeat domain-containing proteins correlate well with the extent of ischemic damage to the heart and may prove to be suitable markers of previous myocardial infection [34], especially in diabetes-associated cardiomyopathy [35]. The notion that Asb genes drive muscle repair and expansion is further supported by observations in murine muscle precursor cells. Mouse C2C12 myoblasts, upon application of differentiation medium, synchronously withdraw from the cell cycle, elongate, adhere, and finally fuse together to form myotubes exhibiting most of the mechanobiochemical adaptations associated with fully differentiated muscle [36]. Thus, this system represents a valuable model to study the effect of Asb proteins on muscle cell differentiation, and the extent of terminal differentiation can be assessed by activation of the muscle creatin kinase (MCK) promoter [37] or the expression of myosin heavy chain [38]. Importantly, expression of human ASB5, ASB9, or ASB11 inhibits transactivation of the MCK promoter and expression of myosin heavy chain upon induction of muscle differentiation, but increased expression of myogenin, a marker of proliferative early myogenesis in mammals [39]. Together, these observations showed that forced expression of Asb genes prevents terminal myocyte differentiation but not myoblast differentiation of muscle precursors not only in zebrafish, but also in other vertebrates, including mammals. Compartment expansion is intimately linked to cancer. Upregulation of ASB9 expression is directly associated with overall survival in colorectal cancer and is a useful biomarker to predict aggressive disease and prognosis [40]. In addition, copy number alterations of ASB13, as well as overall ASB13 protein levels, are sensitive biomarkers to predict the outcome of breast cancer in humans, suggesting that multiple Asb genes have a role in driving cancer [41]. In apparent agreement with a role of six ankyrin repeat containing proteins in regulating compartment size is that genetic polymorphisms in ASB9 and ASB13 are associated with an increase in the size of adipose compartment and morbid obesity 42, 43. Thus, the six-ankyrin repeat domain-containing Asb genes are intimately linked to both physiological and pathophysiological compartment expansion.