TRPC channels in exercise-mimetic therapy

Abstract

Physical exercise yields beneficial effects on all types of muscle cells, which are essential for the maintenance of cardiovascular homeostasis and good blood circulation. Daily moderate exercise increases systemic antioxidative capacity, which can lead to the prevention of the onset and progression of oxidative stress-related diseases. Therefore, exercise is now widely accepted as one of the best therapeutic strategies for the treatment of ischemic (hypoxic) diseases. Canonical transient receptor potential (TRPC) proteins are non-selective cation channels activated by mechanical stress and/or stimulation of phospholipase C-coupled surface receptors. TRPC channels, especially diacylglycerol-activated TRPC channels (TRPC3 and TRPC6; TRPC3/6), play a key role in the development of cardiovascular remodeling. We have recently found that physical interaction between TRPC3 and NADPH oxidase (Nox) 2 under hypoxic stress promotes Nox2-dependent reactive oxygen species (ROS) production and mediates rodent cardiac plasticity, and inhibition of the TRPC3-Nox2 protein complex results in enhancement of myocardial compliance and flexibility similar to that observed in exercise-treated hearts. In this review, we describe current understanding of the roles of TRPC channels in striated muscle (patho)physiology and propose that targeting TRPC-based protein complexes could be a new strategy to imitate exercise therapy.

Keywords: Plasticity; Protein-protein interaction; Redox signaling; Remodeling; Transient receptor potential.

Fig. 1

Canonical transient receptor potential (TRPC) channels function as mechanosignal transducers to Nox proteins during skeletal muscle contraction. Nox-mediated reactive oxygen species (ROS) production plays critical roles in skeletal muscle homeostasis

Fig. 2

Canonical transient receptor potential (TRPC) channel function in striated muscle cells. TRPC1 channel activity is regulated via interaction with the dystrophin-associated protein complex (DAPC). TRPC1 also functions as a Ca²⁺ leak channel in the sarcoplasmic reticulum. TRPC3 channels are localized in T-tubules

Fig. 3

TRPC3-Nox2 coupling in cardiomyocytes. TRPC3 co-localizes and interacts with Nox2 in T-tubules in cardiomyocytes. Reactive oxygen species (ROS) oxidize ryanodine receptors (RyRs), which sensitizes them to Ca²⁺ during diastole

Fig. 4

Physiological significance of canonical transient receptor potential (TRPC) channels in exercised human body. Exercise may increase the abundance of TRPCs and Nox proteins in skeletal muscle, while it may downregulate TRPC3 and Nox2 in the heart. Exercise-induced upregulation of TRPCs is concomitant with the upregulation of antioxidants, which may lead to a reduction of disease risk in remote organs, such as the cardiac pathological remodeling mediated by the TRPC3-Nox2 complex formation