iPLA2β deletion normalizes SOCE, preserves Ca2+ homeostasis, and protects against denervation-induced muscle mass and strength loss, revealing that iPLA2β may be a critical link between oxidative stress and Ca2+ dysregulation and a promising target for mitigating muscle dysfunction during denervation.
Abstract
Sarcopenia, the age-related loss of skeletal muscle mass and strength, is a major cause of frailty and disability, with neuromuscular denervation as a key contributor. Bioactive lipid mediators, including lipid hydroperoxides and oxylipins, contribute to denervation-induced muscle atrophy and dysfunction. Here, we identify calcium-independent phospholipase A2β (iPLA2β) as a novel regulator of store-operated calcium ion (Ca2+) entry (SOCE), a critical process for maintaining Ca2+ homeostasis via stromal interaction molecule 1 (STIM1) and Orai1 coupling in skeletal muscle. Using muscle-specific iPLA2β knockout (miPLA2βKO) mice, we show that iPLA2β interacts with STIM1-Orai1 coupling to modulate SOCE. Denervation elevates iPLA2β, hyperactivating SOCE and causing Ca2+ overload through oxidative impairment of regulators such as SERCA. iPLA2β deletion normalizes SOCE, preserves Ca2+ homeostasis, and protects against denervation-induced muscle mass (5%) and strength loss (50%). These findings reveal that iPLA2β may be a critical link between oxidative stress and Ca2+ dysregulation and a promising target for mitigating muscle dysfunction during denervation.
ABSTRACT Store-operated calcium entry (SOCE) mediated by STIM and Orai proteins is a fundamental Ca2+ influx mechanism that critically regulates intracellular calcium homeostasis and participates in cardiovascular pathophysiology. Upon endoplasmic reticulum Ca2+ store depletion, STIM1/2 activate plasma membrane Orai1/3 channels, initiating Ca2+ entry that drives vasoconstriction, smooth muscle proliferation, platelet activation, and cardiac hypertrophy. Dysregulated SOCE is closely associated with hypertension, atherosclerosis, pulmonary hypertension, and thromboembolic disorders. However, SOCE is not a simple binary pathway but operates within a complex regulatory network. Beyond the core STIM-Orai axis, auxiliary proteins including transient receptor potential canonical 1 (TRPC1), tetraspanin 18 (Tspan18), tropomyosin 3 (TPM3), SOCE-associated regulatory factor (SARAF), and A-kinase anchoring protein 79/150 (AKAP79/150) modulate SOCE amplitude, kinetics, and downstream signaling in a cell- and context-dependent manner. Moreover, the functional consequences of SOCE are highly heterogeneous: Orai1 protects adult cardiomyocytes but promotes pathological hypertrophy in neonatal cells, posing a therapeutic dilemma. Although preclinical studies have shown efficacy of SOCE inhibitors, clinical translation remains hindered by poor isoform selectivity, suboptimal pharmacokinetics, lack of tissue-specific delivery, disease-stage-dependent effects, and absence of validated biomarkers. Importantly, recent evidence has definitively ruled out amlodipine-induced CRAC channel activation at therapeutic concentrations, confirming it as an experimental artifact. This review systematically summarizes the molecular complexity, functional diversity, and translational barriers of STIM/Orai-mediated SOCE, aiming to inform precision therapeutic strategies for cardiovascular diseases.
The SERCA2-RAS-TGF-β/Smad-S100a4 signaling axis emerges as a highly promising therapeutic target for mitigating disuse-induced skeletal muscle wasting.
Fei Nan, Siyao Liu, Shunyi Lei et al.· Redox Biology· 0 citations
Results showed that FMN improved lean mass, grip strength, mitochondrial membrane potential, and ATP production, while reducing ROS and ferroptosis by regulating ACSL4, GPX4, and SLC7A11.
Xiao Wang, Linhan Zhong, Jun Yang et al.· International Journal of Bio...· 0 citations
Reduced expression and activity of cardiac sarco/endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a), causing intracellular calcium dyshomeostasis, are regarded as hallmarks of heart failure (HF). However, effective SERCA2a-targeted therapies for HF treatment have not been identified. Here, we show that fluorofenidone, previously reported to enhance cell shortening, contraction and relaxation of cardiomyocytes by nearly 100%, prevents the progression of pressure overload-induced HF. Combining drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) approaches, we identify SERCA2a as a direct binding partner of fluorofenidone. Mechanistically, fluorofenidone attenuates the binding of WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) to SERCA2a and inhibits WWP1-mediated K27-linked polyubiquitination of SERCA2a. Moreover, Gln758, Asp812 and Glu917 are essential for the fluorofenidone-SERCA2a interaction. SERCA2a knockdown markedly attenuated the cardioprotective effects of fluorofenidone on pressure overload-induced HF in male mice. Together, these findings highlight the therapeutic potential of fluorofenidone for HF treatment. Nevertheless, further preclinical and clinical studies are required to fully evaluate its in vivo efficacy and safety before clinical translation. Reduced expression and activity of cardiac sarco/endoplasmic reticulum Ca2 + -ATPase 2a (SERCA2a) are regarded as hallmarks of heart failure. Here, the authors show how the SERCA2a-targeted small-molecule agent fluorofenidone protects against pressure overload-induced heart failure.
Quan Liu, Huayang Li, Jiantao Chen et al.· Nature Communications· 0 citations
Heart failure with preserved ejection fraction (HFpEF) is a major heart failure phenotype in type 2 diabetes mellitus, yet therapies directed at its underlying cardiomyocyte mechanisms remain limited. This review focuses on how diabetic metabolic, inflammatory, and structural stress remodel cardiomyocyte Ca2+ handling. Impaired sarcoplasmic reticulum Ca2+ reuptake, enhanced diastolic Ca2+ leak, reduced sarcolemmal Ca2+ extrusion, and disrupted mitochondrial Ca2+-energy coupling collectively delay Ca2+ clearance and sustain elevated end-diastolic cytosolic Ca2+, thereby contributing to impaired diastolic relaxation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors may improve Na+-Ca2+ coupling by reducing sodium-hydrogen exchanger 1 (NHE1)- and late Na+ current-mediated Na+ overload, whereas metabolic interventions such as ketone supplementation and glucagon-like peptide-1 receptor agonists may support mitochondrial energetics and Ca2+ clearance. More direct approaches, including modulation of Ca2+-handling proteins, ryanodine receptor 2 (RyR2) stabilization, sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) restoration, and repair of T-tubule-associated microdomains, remain largely preclinical or early translational. Advancing this field will require human myocardial validation, biomarkers linked to specific Ca2+ defects, and stratification of patients according to the dominant mechanism of Ca2+ dysregulation.
Hypercapnia, elevated carbon dioxide (CO2), is common in advanced chronic obstructive pulmonary disease (COPD) and predicts poor clinical outcomes. Traditionally considered a consequence of disease severity, hypercapnia may drive disease progression by promoting airway dysfunction. Here, we show that hypercapnia acts as an active stressor, driving airway smooth muscle (ASM) constriction through a stromal interaction molecule 1 (STIM1)-dependent pathway. Hypercapnia rapidly activates ERK, triggering sarcoplasmic reticulum calcium (Ca2+) release via phosphorylation of the inositol 1,4,5-trisphosphate receptor. ERK also induces nuclear translocation of the transcription factor c-Fos, enhancing STIM1 transcription. These responses were observed under both supraphysiological (~120 mmHg) and clinically relevant (50-60 mmHg) hypercapnia. Increased STIM1 abundance sustains store-operated Ca2+ entry (SOCE), amplifying ASM signaling. In mice, hypercapnia increased ASM and airway contractility in a STIM1-dependent manner. Human genetic analyses revealed noncoding STIM1 variants associated with reduced lung expression that were enriched in COPD patients. These variants correlated with lower airway resistance under normocapnia; however, this benefit was lost during hypercapnia, indicating a potential gene-environment interaction. Together, our findings position STIM1 as a key mechanistic node linking hypercapnia to Ca2+ dysregulation and airway obstruction, defining a CO2-ERK-STIM1-SOCE axis with translational relevance to chronic lung disease.
M. Shigemura, Vitalii Kryvenko, Jennifer A. Pacheco et al.· JCI Insight· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
