On the footsteps of Triadin and its role in skeletal muscle

Abstract

Calcium is a crucial element for striated muscle function. As such, myoplasmic free Ca(2+) concentration is delicately regulated through the concerted action of multiple Ca(2+) pathways that relay excitation of the plasma membrane to the intracellular contractile machinery. In skeletal muscle, one of these major Ca(2+) pathways is Ca(2+) release from intracellular Ca(2+) stores through type-1 ryanodine receptor/Ca(2+) release channels (RyR1), which positions RyR1 in a strategic cross point to regulate Ca(2+) homeostasis. This major Ca(2+) traffic point appears to be highly sensitive to the intracellular environment, which senses through a plethora of chemical and protein-protein interactions. Among these modulators, perhaps one of the most elusive is Triadin, a muscle-specific protein that is involved in many crucial aspect of muscle function. This family of proteins mediates complex interactions with various Ca(2+) modulators and seems poised to be a relevant modulator of Ca(2+) signaling in cardiac and skeletal muscles. The purpose of this review is to examine the most recent evidence and current understanding of the role of Triadin in muscle function, in general, with particular emphasis on its contribution to Ca(2+) homeostasis.

Keywords: Calcium release; Excitation-contraction coupling; FKBP12; Resting calcium; Ryanodine receptor; Triadin-null.

Figure 1

Genomic structure of mouse Trdn gene. A: Schematic representation of mouse Triadin cDNA structure within the context of the Triadin genomic locus according to the Mouse Genomic Informatics (MGI) gene model[60]; B: Splicing patterns of Triadin. Exons are shown as boxes and introns as lines. The exon splicing pattern that gives rise to the three cardiac Triadin isoforms currently cloned (MT1, MT2 and MT3) as well as the predicted full-length skeletal isoform (Trdn95) are indicated. Size and number of exon boxes in the genomic locus (blue) are not showed in actual scale.

Figure 2

Proposed model of Ca²⁺ regulation by Triadin in wild-type and Triadin-null skeletal muscle. Lack of Triadin binding to type-1 ryanodine receptor (RyR1) indirectly affects FKBP12/RyR1 interaction causing, on the one hand, an increase in RyR1 channel gating and, on the other hand, a weakening of the DHPRα_1S/RyR1 orthograde signaling. Dysregulation of RyR1 activity of Triadin-null cells leads to enhanced SR Ca²⁺ leakage and subsequent reduction in SR Ca²⁺ content. In addition, lack of Triadin expression activates Ca²⁺ entry pathways that are both store-dependent and store-independent (sensitive to TRPC/Orai-1 inhibitors). Ca²⁺ entry and SR Ca²⁺ leakage could contribute independently to elevate myoplasmic [Ca²⁺]_rest.