Nicotinic acid adenine dinucleotide phosphate regulates skeletal muscle differentiation via action at two-pore channels

Abstract

Calcium signaling is essential for the differentiation of many cell types, including skeletal muscle cells, but its mechanisms remain elusive. Here we demonstrate a crucial role for nicotinic acid adenine dinucleotide phosphate (NAADP) signaling in skeletal muscle differentiation. Although the inositol trisphosphate pathway may have a partial role to play in this process, the ryanodine signaling cascade is not involved. In both skeletal muscle precursors and C2C12, cells interfering with NAADP signaling prevented differentiation, whereas promoting NAADP signaling potentiated differentiation. Moreover, siRNA knockdown of two-pore channels, the target of NAADP, attenuated differentiation. The data presented here strongly suggest that in myoblasts, NAADP acts at acidic organelles on the recently discovered two-pore channels to promote differentiation.

Two-pore channel 1 interacts with citron kinase, regulating completion of cytokinesis

“…3,4,7 In plants, studies of Ca 2C release in Arabidopsis identified AtTPC1 as a channel 8 that mediates the slow vacuolar current, 9 regulating germination and stomatal movement. 10 TPCs have been shown to regulate differentiation, 11 smooth muscle contraction 12 and endothelial cell activation, 13 consistent with previous studies implicating nicotinic acid adenine dinucleotide phosphate (NAADP)-induced Ca 2C release in these events, [14][15][16] and supported by several overexpression, knockdown and knockout models. 3,4,6,17 Regulation and affinity of TPC ion channels is a contentious issue.…”

Identification of Two-pore Channel 2 as a Novel Regulator of Osteoclastogenesis

“…This often leads to recruitment of further Ca 2ϩ release from the ER through IP 3 Rs or ryanodine receptors (12,13). TPC2 is required for myocyte differentiation (14,15). This channel is also involved in autophagy in astrocytes (16).…”

Two-pore channels (TPCs): Novel voltage-gated ion channels with pleiotropic functions

“…29 TPCs have an important role in neuronal development; in fact, it has been shown a liposomal delivery of NAADP mediated release of Ca 2C from acidic Ca 2C stores, and that this stimulus was enough to drive differentiation of the PC12 cells (derived from a pheochromocytoma of the rat adrenal medulla) to a neuronal-like phenotype. 74 Moreover, Zhang et al 28 have observed that the expression of TPC2 was markedly decreased during the initial stem cell entry into neural progenitors, and that it was gradually rebounded during the late stages of neurogenesis.…”

“…Additionally, TPC2 K D accelerated mouse stem cell differentiation into neural progenitors, but inhibited these neural progenitors from committing to neurons, and had no effect on the differentiation of astrocytes and oligodendrocytes of mouse stem cells. 28 Otherwise, in skeletal muscle cells, Aley et al 29 studies strongly supported a role of the TPCs in the differentiation process of skeletal muscle cells: treatment of C2C12 cells (a mouse myoblast cell line) with TPC2 siRNA resulted in a decreased differentiation and fusion index, 29 while TPC1 siRNA treated C2C12 cells showed a reduced number of multinucleated myotubes; although the number of nuclei per myotube did not differ from control cells and, additionally, treatment with Ned-19 (an NAADP agonist) interfere with the differentiation of C2C12 cells. 29 Ultimately, it has been demonstrated that the expression levels of TPC2 were enhanced during osteoclast differentiation and, 30 although the mechanism which causes this suppression remains to be determined, current findings indicate that TPC2 could be a differentiation indicator of osteoclastic cells.…”

“…Today it is known that TPCs have a role not only in ion signaling but also in intracellular vesicle trafficking, [18][19][20] participating in a wide range of pathophysiological processes; that is why in the last years TPCs have received an increased attention from the main journals in the field, and they have been related to the regulation of many biological functions at different levels, including pancreatic b-cell function, 21,22 thermogenesis, 23 nutrient sensing, 6 endolysosomal transport and functions, 19,20 exocytosis, 24,25 cytokinesis, 26 fertilization and embryogenesis, 27 cell differentiation, [28][29][30][31] angiogenesis, 32 endothelium activation mediated by histamine, 33 smooth muscle contraction, 34 autophagy, [35][36][37][38][39][40] skin pigmentation, 41 or even to the Ebola virus infection mechanism. 42 As well, recent studies have suggested their possible implication in the pathogenesis of Alzheimer disease, 36 46 Thus, TPCs have become attractive therapeutic targets, although it is necessary to go deeper into their main functions and mechanisms of action not only to clinically relevant compounds could be designed but also to understand the pathophysiology of an increased wide range of diseases related to TPCs function/dysfunction.…”