Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle viaK_Ca1.1 upregulation

Abstract

Summary KC a1.1 regulates smooth muscle contractility by modulating membrane potential, and age‐associated changes in KC a1.1 expression may contribute to the development of motility disorders of the gastrointestinal tract. Sphingolipids (SLs) are important structural components of cellular membranes whose altered composition may affect KC a1.1 expression. Thus, in this study, we examined whether altered SL composition due to aging may affect the contractility of gastric smooth muscle (GSM). We studied changes in ceramide synthases (CerS) and SL levels in the GSM of mice of varying ages and compared them with those in young CerS2‐null mice. The levels of C16‐ and C18‐ceramides, sphinganine, sphingosine, and sphingosine 1‐phosphate were increased, and levels of C22, C24:1 and C24 ceramides were decreased in the GSM of both aged wild‐type and young CerS2‐null mice. The altered SL composition upregulated KC a1.1 and increased KC a1.1 currents, while no change was observed in KC a1.1 channel activity. The upregulation of KC a1.1 impaired intracellular 2+ mobilization and decreased phosphorylated myosin light chain levels, causing GSM contractile dysfunction. Additionally, phosphoinositide 3‐kinase, protein kinase C ζ, c‐Jun N‐terminal kinases, and nuclear factor kappa‐B were found to be involved in KC a1.1 upregulation. Our findings suggest that age‐associated changes in SL composition or CerS2 ablation upregulate KC a1.1 via the phosphoinositide 3‐kinase/protein kinase C ζ/c‐Jun N‐terminal kinases/nuclear factor kappa‐B‐mediated pathway and impair 2+ mobilization, which thereby induces the contractile dysfunction of GSM. CerS2‐null mice exhibited similar effects to aged wild‐type mice; therefore, CerS2‐null mouse models may be utilized for investigating the pathogenesis of aging‐associated motility disorders.

A tissue‐specific screen of ceramide expression in aged mice identifies ceramide synthase‐1 and ceramide synthase‐5 as potential regulators of fiber size and strength in skeletal muscle

“…Recent evidence suggests that ceramides play a role for the aging of gastric smooth muscle. The levels of CerS2 mRNA were significantly smaller, and CerS4‐6 levels were greater in gastric smooth muscle of aged mice associated with contractile dysfunction (Choi et al, ). In skeletal muscle of mice fed with high‐fat diet, CerS1‐derived C18 ceramide promoted systemic insulin resistance (Turpin‐Nolan et al, ), indicating an impact of ceramide in skeletal muscle metabolism.…”

K Ca 3.1 upregulation preserves endothelium‐dependent vasorelaxation during aging and oxidative stress

“…S5C). We previously reported that the CerS2 ablation‐induced alteration in the levels of CerSs and sphingolipid composition is similar to aging‐related alteration in these measurements in mice (Choi et al ., 2015b). As CerS5 was upregulated in CerS2 null mice, we examined the effects of CerS5 transfection on levels of antioxidant enzymes and K Ca 3.1 in wild‐type MAECs (Fig.…”

“…We then examined whether sphingosine or S1P affects K Ca 3.1 levels because sphingosine or S1P levels were increased in CerS2 null (Fig. S5C) and aged (Choi et al ., 2015b) mice. Exogenously added sphingosine (Fig.…”

“…In addition, sphingolipid composition and the activities of antioxidant enzymes (SOD, catalase, GPX) were altered in aged rats or rabbits (Lightle et al ., 2000; Cejkova et al ., 2004). Furthermore, our previous study showed that the levels of ceramide synthases (CerSs) and sphingolipid composition are altered with aging in mice and that aging‐related alteration in the levels of CerSs and sphingolipid composition is similar to the alteration induced by CerS2 ablation (Choi et al ., 2015b). These results suggest that ROS (which are generated as a result of altered sphingolipid composition) play an important role in the aging process, and that CerS2 null mice can allow us to investigate aging‐related and altered sphingolipid composition‐induced changes in cellular functions.…”

Budding Yeast: An Ideal Backdrop for In vivo Lipid Biochemistry

“…In addition, organization and dynamics of lipids in membranes of different subcellular structures have not been probed accurately. Interestingly, dynamics of lipid metabolism is altered during cell cycle progression in mammalian fibroblast cells (Singh et al, 2013) and aging (Choi et al, 2015). For example, about 40% increase was observed in cholesterol content in rat fibroblast cells (Singh et al, 2013) while sphingolipid levels are dysregulated during aging rats and mice (Sacket et al, 2009; Babenko and Shakhova, 2014; Mc Auley and Mooney, 2015).…”