TRPC channels in exercise-mimetic therapy
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.
KeywordsTransient receptor potential Redox signaling Remodeling Plasticity Protein-protein interaction
Moderate exercise produces pleiotropic effects on health, by stimulating systemic blood circulation and energy metabolism and refreshing the mind. Exercise is also known to reduce cardiovascular risk factors related to many pathological conditions. Although primarily affecting skeletal muscle functions such as increasing the rate of glucose uptake, physical exercise gives rise to several beneficial effects on other remote organs through blood circulation-dependent organ-organ interactions. A critical risk factor for the development of pathological conditions is the increase of oxidative stress caused by overproduction of reactive oxygen species (ROS). ROS are mainly produced as a byproduct of uncoupling of the respiratory chain during mitochondrial dysfunction, or enzymatically, by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) proteins. Physical exercise is well known to induce ROS production, but it also triggers upregulation of antioxidative systems leading to acquisition of resilience against many diseases . We have also revealed that long-term physical exercise reduces the expression of Nox2 in the heart . This review introduces the (patho)physiological roles of Nox and canonical transient receptor potential (TRPC) proteins in skeletal muscles, mainly focusing on the mechanisms common to other muscular organs (i.e., the cardiovascular system), and proposes a novel strategy for imitating exercise therapy.
Roles of Nox proteins in skeletal muscle
There are seven isoforms of Nox proteins. Nox1, Nox2 and Nox4 are reportedly expressed in skeletal muscle . Nox2 and Nox4 are predominantly expressed in the heart. In resting conditions, Nox2 only interacts with the p22phox subunit of the NADPH oxidase, which promotes the expression of Nox2 by preventing its proteasomal degradation. Upon cellular activation, the other cytoplasmic subunits p67phox, p40phox and p47phox, and the small G protein Rac1 are recruited and activate Nox2 protein. Among the cytoplasmic subunits, p47phox is the main regulator of the Nox2 complex formation. To form a complex, phosphorylation of p47phox is necessary. Phosphorylation of p47phox is reported to be mediated by protein kinase C, mitogen-activated protein kinases and p21-activated kinase . The importance of Nox proteins in skeletal muscle is highlighted by their role in contraction-induced ROS production . It is well known that muscle contraction produces ROS and reactive nitrogen species [26, 59]. ROS production plays important roles in skeletal muscle, for example, increasing the activities of antioxidant defense enzymes, force production, glucose uptake and insulin signaling [25, 45]. Application of hydrogen peroxide (H2O2) induces a similar gene expression profile to that of contracting a skeletal muscle, suggesting that muscle contraction signals are mainly conveyed by H2O2 . The regulation and physiological relevance of Nox proteins in skeletal muscle have been reviewed in detail elsewhere [15, 27].
Roles of TRPC channels in skeletal muscle
The trp gene was first identified in 1989 as a causative gene mutant affecting phototransduction in Drosophila . Twenty-eight mammalian TRP homologues have been identified, and these are subdivided into six subfamilies based on their genetic and functional similarities: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin) and TRPA (ankyrin). TRP proteins commonly possess six transmembrane domains and a preserved 25-amino acid sequence called the ‘TRP domain’. There are several reports demonstrating the involvement of TRP channels in exercised skeletal muscles. TRPM8 activation enhances exercise endurance and reduces blood lactic acid and triglycerides by upregulating uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) in skeletal muscles . TRPV1 activation by dietary capsaicin increases the proportion of oxidative fibers, promotes mitochondrial biogenesis, enhances exercise endurance and prevents high-fat diet-induced metabolic disorders via an increase of PGC1α expression . TRPV1 is reportedly activated by peroxynitrite, a reaction product of nitric oxide and superoxide, and mediates overload-induced skeletal muscle hypertrophy [23, 24]. These TRP channels are likely to function downstream of mechano-signal transduction in skeletal muscle contraction.
TRPC1 mediates SOCE in the C2C12 myoblast cell line. siRNA-mediated knockdown of TRPC1 suppressed myotube formation of C2C12 cells. Interestingly, TRPC1 mRNA expression transiently increased immediately after the onset of differentiation (1 day) and returned to the basal level 4–6 days after the start of differentiation. Increased TRPC1 activity was correlated with the activity of calpain . TRPC1 proteins were also transiently upregulated 24 h after the induction of differentiation and returned to the basal level at 72 h. Formigli et al. also demonstrated that TRPC1 is not only activated by store depletion, but also mechanical stretch, in C2C12 cells. Mechanical stretch facilitates myoblast differentiation in a sphingosine 1-phosphate (S1P)-dependent manner . S1P application to C2C12 cells markedly increased TRPC1 expression, concomitant with an increase in stretch-activated channel expression . S1P-mediated activation of TRPC1 induces m-calpain activity and subsequent expression of connexin43 . TRPC1 overexpression in C2C12 cells increased the rate and amplitude of SOCE. Interestingly, in those cells levels of stromal interaction molecule 1 (STIM1) and sarcoendoplasmic reticulum calcium ATPase (SERCA) expression were lower, which resulted in insufficient Ca2+ clearance after the depolarization-induced Ca2+ increase. Furthermore, Ca2+ dyshomeostasis induced by TRPC1 overexpression attenuated the nuclear factor of activated T cells (NFAT) signaling pathway and myotube formation . In human myoblasts, TRPC1 downregulation caused by siRNA expression or overexpression of a dominant negative mutant clearly suppressed SOCE, myogenic driver MEF2 expression and fusion of myoblasts into myotubes . TRPC1 activation is regulated by STIM1L, a long isoform of STIM1 . TRPC1 forms a heterotetramer with TRPC3 via interaction at the ankyrin repeat of TRPC3. The short protein comprising the N-terminal 37 amino acids of TRPC3 can inhibit TRPC1-TRPC3 heteromultimerization, which reduces resting cytosolic Ca2+ in murine skeletal myotubes .
TRPC1 is highly expressed in skeletal muscle stem cell satellite cells. Fibroblast growth factor 2 (FGF2) treatment increased the intracellular Ca2+ concentration and nuclear accumulation of NFATc3 and NFATc2 in these cells. The broad TRPC blocker SKF-96365 inhibits these responses . Therefore, TRPC1 plays a critical role in the regeneration process following muscle injury, by contributing to satellite cell activation.
A TRPC1 knockout (TRPC1−/−) mouse showed decreased endurance for physical activity. Histological analysis showed a reduced cross-sectional area of skeletal muscle fibers and myofibrillar protein content. Isolated muscle fibers from TRPC1+/+ mice showed instances of small, spontaneous activity which are absent in those from TRPC1−/− mice. In primary muscle fibers, TRPC1 does not participate in store-operated or stretch-activated calcium influx. However, there is a marked reduction of force production in both the soleus and extensor digitorum longus (EDL) muscles of TRPC1−/− mice. Furthermore, muscle fatigue is accelerated in the soleus and EDL muscles from TRPC1−/− mice compared with those from TRPC1+/+ mice . TRPC1-YFP transgenic mice also exhibited no significant differences in the electrical properties of skeletal muscle fibers. However, calcium clearance after repetitive contractile stimuli was delayed in TRPC1−/− mice, and responses to cyclopiazonic acid were enhanced, suggesting that TRPC1 functions in the intracellular Ca2+ store membrane as a calcium leak channel (Fig. 2) . In mdx mice, the diaphragm muscle had higher expression of TRPC1 compared with the sternomastoid and limb muscles. The levels of TRPC1 expression in mdx mice correlate well with the degree of pathological changes observed in skeletal muscles, i.e., the diaphragm shows the most severe pathological phenotype . In a model of cardiotoxin-induced muscle injury, TRPC1−/− mice showed significant hypotrophy and increased proportions of centrally nucleated muscle fibers. It is suggested that TRPC1−/− myoblasts cannot correctly differentiate into myotubes because myogenic factors are downregulated. These phenotypes of TRPC1-depleted skeletal muscle were attributed to the suppression of the phosphatidylinositol-3-kinase-mammalian target of rapamycin (PI3K-mTOR) pathway. The TRPC1-mediated Ca2+ increase is critical for the activation of PI3K . TRPC1−/− muscle is resistant to repeated eccentric contraction. This phenotype is similar to that observed in muscle treated with streptomycin, a stretch-activated channel inhibitor. Although force reduction caused by repeated eccentric contraction was not affected by the absence of TRPC1, the loss of sarcolemmal proteins and reduced resting stiffness were suppressed by both TRPC1 knockout and streptomycin treatment, suggesting that TRPC1 contributes to stretch-activated Ca2+ entry in skeletal muscle .
The mechanical unloading seen in long-term bed rest patients and astronauts evokes muscle loss via oxidative stress. Ca2+ influx is critical for myoblast proliferation and controls exit from the G2/M phase of the cell cycle. Simulated microgravity, an in vitro model of mechanical unloading in space, reduced the expression of TRPC1 . Hind limb unloading induces soleus muscle atrophy and reduction of tetanic force. During unloading, TRPC1 protein expression was reduced [84, 91] and recovered 14 days after reloading. The recovery of TRPC1 expression was preceded by and dependent on NFAT pathway activation. siRNA-mediated TRPC1 downregulation in vivo attenuated skeletal muscle regrowth of the soleus muscle, manifested by reduced cross-sectional area and type I myosin heavy chain expression . These results suggest that proper mechanical signaling is important for skeletal muscle homeostasis, and TRPC1 plays a critical role in this.
Consistent with the accumulated data from the mdx mouse model, human myoblasts isolated from Duchenne muscular dystrophy (DMD) patients showed a significant increase in SOCE but no increase in levels of TRPC1, Stim1 or Orai1. However, pharmacological inhibition of phospholipase C or protein kinase C, which are components of a signaling complex with TRPC1, restores SOCE to the normal level .
Omega-3 fatty acid administration slows DMD progression, partly due to a reduction in TRPC1 expression .
Step up/down exercise involves concentric contraction in the right vastus lateralis (VL) muscle and eccentric contraction in the left VL muscle. Satellite cells in the left VL muscle only are activated, as indicated by an increase of expression of hepatocyte growth factor and MyoD, a myogenic transcription factor. As stated above, TRPC1 likely plays an important role in satellite cell activation. Consistent with this, TRPC1 expression was significantly increased in satellite cells of the left VL muscle, suggesting that eccentric but not concentric exercise activates satellite cells in a TRPC1-dependent manner .
TRPC3 expression is relatively high in skeletal muscle tissue . TRPC3 mRNA expression was increased after 3–4 days of differentiation in the C2C12 myoblast cell line [10, 40]. In the model of hind limb unloading, TRPC3 expression was lower in the early phase after the reloading process , suggesting that TRPC3 is downregulated during the regeneration process, possibly because undifferentiated myoblasts have lower levels of TRPC3 expression. TRPC3 channel expression in skeletal muscle is increased after neuromuscular activity by NFAT-dependent transcriptional upregulation. TRPC3 expression is higher in muscles enriched in slow oxidative fibers than those enriched in fast glycolytic fibers. Voluntary free-wheel running increased TRPC3 expression either 1 or 3 weeks after treatment in both the soleus and EDL muscles. Furthermore, electrical neurostimulation at 10 Hz increased levels of TRPC3 transcripts in the tibialis anterior (TA) muscle . TRPC3 expression was significantly increased in TRPV4−/− mouse skeletal muscle, in which the proportion of oxidative fibers was also increased . These results suggest the importance of TRPC3 channels, especially in oxidative slow muscle fibers. TRPC3 interacts with ryanodine receptor type 1 (RyR1) in skeletal muscle (Fig. 2) [35, 80]. Loss of TRPC3 reduces the expression of RyR1, and vice versa , suggesting that TRPC3 plays a critical role in the modulation of RyR1. Indirect positive regulation of RyR by TRPC3 via Nox2-mediated ROS production has also been demonstrated in cardiomyocytes [29, 63, 64]. This TRPC3-Nox2-RyR coupling might also play important roles in skeletal muscle. TRPC3 also interacts with glucose transporter 4 (Glut-4) in T-tubules, and silencing of TRPC3 by siRNA reduced insulin-mediated glucose uptake by skeletal muscle. In accordance with these data, obese mice showed less oleoyl-acyl-sn-glycerol (OAG)-induced TRPC3 current . TRPC3 also interacts with mitsugumin 29 (MG29), which is involved in the fatigue and aging processes of skeletal muscle. TRPC3-binding-deficient MG29 expression reduced the excitation-induced Ca2+ response in skeletal myotubes, indicating that MG29 plays a critical role in the regulation of TRPC3 channel function in skeletal muscle (Fig. 2) . It has also been demonstrated that MG53 can interact with TRPC3 in skeletal muscle . Myoblasts from muscular dysgenic mouse skeletal muscle failed to differentiate into myotubes when TRPC3 was knocked down .
TRPC3-overexpressing transgenic mice show a pathological phenotype similar to muscular dystrophy, suggesting that excess Ca2+ influx mediated by TRPC channels is sufficient to cause the disease. Using a TRPC6 dominant negative mutant, suppression of TRPC channels ameliorated the dystrophic myofibers of delta-sarcoglycan-null (Scgd−/−) mice .
TRPC4 is also expressed in skeletal muscle cells, and its expression is increased in mdx mice. TRPC4 can form a heterotetramer with TRPC1. Similar to TRPC1, TRPC4 can interact with alpha-syntrophin and is part of the dystrophin-associated protein complex (DAPC) . In human myoblasts, TRPC4 downregulation by siRNA or overexpression of a dominant negative mutant clearly suppressed SOCE, expression of the myogenic driver MEF2 and fusion of myoblasts into myotubes . In these contexts, TRPC4 couples with TRPC1 and is regulated by STIM1L .
TRPC6 expression is increased in mdx mouse skeletal muscle. Immunostaining revealed that TRPC6 is localized to the sarcoplasmic membrane . Inhibition or deletion of TRPC6 has been reported to blunt the chronic mechanical stress-induced muscular contraction in mouse myocytes with Duchenne muscular dystrophy . TRPC6 expression was significantly increased in TRPV4−/− mouse skeletal muscle, in which the numbers of oxidative fibers were increased more than glycolytic fibers .
Other TRPC channels
Compared with the aforementioned TRPC channels, the roles of TRPC2, TRPC5 and TRPC7 in striated muscles have been less well studied. The expression of TRPC2 is highly restricted, being present only in sperm and the vomeronasal sensory system . Furthermore, TRPC2 is a pseudogene in the human genome. These facts imply that TRPC2 does not contribute significantly to striated muscle physiology. Although its specific function in striated muscles has not been demonstrated even with knockout mice, an involvement of TRPC5 in SOCE in cardiomyocytes has been implied. Recently, we demonstrated that extracellular ATP-induced Ca2+ influx mediated by TRPC5 induces nitric oxide synthase (NOS) activation and protects cardiomyocytes from hypertrophic responses . TRPC7 was originally cloned from a cDNA library of mouse heart . However, its function in cardiac and skeletal muscle remains elusive. The pathological significance of the closely related homologues TRPC3 and TRPC6 in striated muscles has been established, as mentioned above. Therefore, TRPC7 might play an important role in striated muscles, although confirmation of this will require a thorough analysis of knockout mice.
Cardioprotective effect of exercise
Physical activity affects not only skeletal muscle cells but also other remote organs. Several factors secreted from skeletal muscle after exercise have been identified, and these are termed myokines . However, not all effects of exercise have been reproduced by the administration of myokines, suggesting that the beneficial effect of exercise is not solely attributable to these limited factors but is a systematic change of whole tissues . The heart is an example of an organ that is very sensitive to the effects of exercise . Patients suffering from heart failure are recommended to engage in supervised physical activity to prevent disease progression and assist cardiac rehabilitation . Therefore, a systematic understanding of the beneficial effects of exercise will be fundamental for developing more effective drugs against cardiac diseases.
Physical exercise as a therapeutic intervention for DOX-induced cardiotoxicity
Doxorubicin (DOX) is a highly effective anticancer agent used to treat a variety of hematologic and solid malignancies [8, 79, 85, 92]. However, its dose-dependent cardiotoxicity limits its clinical use. The cardiotoxic effects of DOX range from asymptomatic increases in left ventricular (LV) wall stress to reductions in ejection fraction, arrhythmias and highly symptomatic congestive heart failure, which are all associated with high mortality [8, 14]. DOX initially causes the heart to shrink, which leads to induction of myocardial apoptosis and interstitial fibrosis at later stages of LV dilated cardiomyopathy [11, 94]. Numerous animal studies suggest that physical exercise training is the best intervention for preventing DOX-induced cardiac toxicity. In sedentary mice, DOX treatment resulted in a statistically significant decrease in heart function compared with control animals, which was mitigated by moderate aerobic exercise during DOX treatment. However, these protective effects of exercise were not observed when exercise was started after completion of DOX treatment. DOX caused not only a decrease in heart function but also cardiac atrophy and loss of body weight that were prevented by exercise, whereas non-trained mice exhibited no changes in these measurements. DOX delivery to the hearts of trained mice was reduced by consistent moderate aerobic exercise before DOX treatment . Resistance training preserved cardiac function and attenuated the α- to β-myosin heavy chain shift that occurs with DOX treatment. No significant differences in lipid peroxidation were observed between sedentary and resistance-trained animals treated with DOX. . Ashraf et al. demonstrated that after endurance training for 3 weeks, the DOX-induced increase in oxidative stress in the heart was significantly attenuated, possibly due to the upregulation of antioxidant systems such as superoxide dismutases (SOD) .
TRPC3-Nox2 coupling in DOX-induced cardiac toxicity
This work was supported in part by a Grant-in-Aid for Scientific Research (16H05092 to M.N.) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). We thank Melony Black, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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