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Systemic Deletion of ARRDC4 Improves Cardiac Reserve and Exercise Capacity in Diabetes
Yoshinobu Nakayama1,2, Satoru Kobayashi3, Aliya Masihuddin1
1Department of Molecular, Cellular and Biomedical Sciences, City University of New York School of Medicine, City College of New York, New York, NY (Y.N., A.M., S.A.A.,A.M.P.B.S., J.Y.).
Insights
Arrestin domain-containing protein 4 (ARRDC4) exacerbates diabetic muscle damage and exercise intolerance by blocking glucose transport. Disrupting the ARRDC4-GLUT1 interaction improves exercise tolerance in diabetic models.
Area of Science:
- Cardiovascular Biology
- Metabolic Diseases
- Molecular Medicine
Background:
- Exercise intolerance is a significant predictor of poor outcomes in diabetes.
- The precise mechanisms linking hyperglycemia to exercise intolerance are not fully understood.
- Previous research identified a role for ARRDC4 and GLUT1 interaction in cardiac metabolism.
Purpose of the Study:
- To investigate the role of ARRDC4 in diabetic cardiac and skeletal myopathy.
- To determine if the ARRDC4-GLUT1 mechanism contributes to broader diabetic complications.
Main Methods:
- Utilized cellular and animal models of diabetes.
- Examined the effects of high glucose on ARRDC4 and GLUT1 expression and localization.
- Assessed cardiac and skeletal muscle function and pathology in ARRDC4-knockout and wild-type diabetic mice.
- Employed cardiac-specific overexpression and genetic mutation models.
Main Results:
- High glucose upregulated ARRDC4, increasing GLUT1 trafficking and blocking glucose transport in cardiomyocytes.
- ARRDC4 upregulation was confirmed in human diabetic muscle cells and diabetic mouse models.
- Deletion of ARRDC4 enhanced glucose transport and mitochondrial respiration, protecting against muscle damage.
- ARRDC4-knockout mice exhibited improved cardiac function and significantly higher exercise endurance under diabetic conditions.
- Disrupting ARRDC4-GLUT1 interaction in mice improved exercise tolerance, suggesting therapeutic potential.
Conclusions:
- ARRDC4 plays a critical role in mediating hyperglycemia-induced damage to cardiac and skeletal muscle.
- This study establishes a novel molecular link between hyperglycemia, myopathy, and exercise intolerance.
- Targeting the ARRDC4-GLUT1 interaction presents a potential therapeutic strategy for diabetic cardiomyopathy and exercise intolerance.
Background:
Exercise intolerance is an independent predictor of poor prognosis in diabetes. The underlying mechanism of the association between hyperglycemia and exercise intolerance remains undefined. We recently demonstrated that the interaction between ARRDC4 (arrestin domain-containing protein 4) and GLUT1 (glucose transporter 1) regulates cardiac metabolism.
Methods:
To determine whether this mechanism broadly impacts diabetic complications, we investigated the role of ARRDC4 in the pathogenesis of diabetic cardiac/skeletal myopathy using cellular and animal models.
Results:
High glucose promoted translocation of MondoA into the nucleus, which upregulated Arrdc4 transcriptional expression, increased lysosomal GLUT1 trafficking, and blocked glucose transport in cardiomyocytes, forming a feedback mechanism. This role of ARRDC4 was confirmed in human muscular cells from type 2 diabetic patients. Prolonged hyperglycemia upregulated myocardial Arrdc4 expression in multiple types of mouse models of diabetes. We analyzed hyperglycemia-induced cardiac and skeletal muscle abnormalities in insulin-deficient mice. Hyperglycemia increased advanced glycation end-products and elicited oxidative and endoplasmic reticulum stress leading to apoptosis in the heart and peripheral muscle. Deletion of Arrdc4 augmented tissue glucose transport and mitochondrial respiration, protecting the heart and muscle from tissue damage. Stress hemodynamic analysis and treadmill exhaustion test uncovered that Arrdc4-knockout mice had greater cardiac inotropic/chronotropic reserve with higher exercise endurance than wild-type animals under diabetes. While multiple organs were involved in the mechanism, cardiac-specific overexpression using an adenoassociated virus suggests that high levels of myocardial ARRDC4 have the potential to contribute to exercise intolerance by interfering with cardiac metabolism through its interaction with GLUT1 in diabetes. Importantly, the ARRDC4 mutation mouse line exhibited greater exercise tolerance, showing the potential therapeutic impact on diabetic cardiomyopathy by disrupting the interaction between ARRDC4 and GLUT1.
Conclusions:
ARRDC4 regulates hyperglycemia-induced toxicities toward cardiac and skeletal muscle, revealing a new molecular framework that connects hyperglycemia to cardiac/skeletal myopathy to exercise intolerance.
