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Persistent Methylmalonate Overload Despite Glycemic Control Drives Mitochondrial Dyshomeostasis and Subclinical Heart Damage in Diabetes

ABSTRACT: Background Heart failure burden is still considerable in diabetes patients despite optimal glycemic control. Metabolic remodeling is involved in this process, but current understanding is still in its infancy. Methylmalonic acid (MMA) is a diagnostic marker of cobalamin (Cbl) deficiency in clinical practice. Paradoxically, MMA elevation-related cardiovascular mortality is more pronounced in diabetic patients with higher Cbl levels. We investigated the mechanisms underlying these contradictory features in diabetic heart and translational relevance. Methods We assessed serum Cbl, MMA, and cardiac biomarkers in 12,751 participants, and the Mmut protein (allosteric enzyme of MMA catabolism) in failing human hearts with diabetes and healthy donors. Cardiomyocyte-specific Mmut knockout and Mmut-overexpressing (delivered by AAV-Mmut with cTnT promoter) mice were subjected to high-fat diet/streptozotocin-induced diabetes. High glucose and/or palmitate stimulation of primary neonatal mouse ventricular cardiomyocytes (NMVMs) imitates diabetic conditions in vitro. Molecular mechanism was explored through RNA sequencing, immunoprecipitation, isotope tracing mass spectrometry and biolayer interferometry assays. Results Higher serum MMA was significantly associated with subclinical heart damage and poor outcomes among adults with diabetes in the absence of Cbl deficiency. Cardiac MMA overload and decreased protein expression of Mmut were observed in humans and mice with diabetes. Notably, MMA dysmetabolism in diabetic mice occurred before detectable cardiac damage and persisted even after glycemic control. Mechanistically, hyperglycemic memory-related molecule miR-499 binds to the mRNA of Mmut and inhibits its expression, leading to MMA overload under diabetes. Mmut knockout amplified cardiac MMA overload and exacerbated disturbances in glycolipid metabolism and mitochondrial quality control in diabetic hearts. Conversely, AAV-Mmut injection significantly reduces MMA load and alleviates the progression of cardiac remodeling in diabetic mice. Isotope tracing identified isoleucine and valine as the main sources of cardiac MMA under diabetes. A restricted-branched chain amino acid diet alleviated diabetes-induced MMA accumulation and heart damage. However, Cbl supplementation did not correct MMA overload in diabetic mice, even at high doses or in activated forms. Strikingly, both clinical and preclinical data showed metformin, a risk factor for Cbl deficiency, may mitigate MMA overload and related heart damage via dual mechanisms—activating AMPK-dependent mitochondrial quality control, enhancing tolerance to MMA insults; and direct Mmut-cobalamin cooperation, promoting MMA clearance independent of AMPK. Conclusions: This study provides a foundation for understanding diabetes-related MMA dysmetabolism as a trigger for subclinical heart damage resistant to glycemic control and Cbl supplementation. Our ﬁndings challenge the prevailing clinical consensus regarding the impacts of Cbl and metformin use on MMA elevation.

ORGANISM(S): Mus musculus

PROVIDER: GSE327065 | GEO | 2026/04/08

REPOSITORIES: GEO

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Project description:BACKGROUND: Clinical studies support that prior hyperglycemia can lead to long-lasting adverse cardiovascular effects, referred to as “glycemic memory”. Several studies support that epigenetic modifications, specifically DNA methylation changes, influenced by altered metabolic pathways, may play a key role in this phenomenon. The objective of this study was to ascertain the gene expression and corresponding DNA methylation signatures linked to glycemic memory, and to investigate if these changes, in long-term, lead to worsened cardiovascular effects upon pressure overload. METHODS AND RESULTS: Using inducible and cardiomyocyte specific GLUT4 overexpression transgenic mice, we induced glucose delivery for 2 weeks, followed by another 2 weeks of basal uptake. Next, we employed RNA-sequencing and reduced representation bisulfite sequencing and discovered differential gene expression and DNA methylation signatures that persisted even after cellular glucose levels reverted to normal. Significant changes across both expression and methylation enriched pathways associated with adverse cardiac events, indicating a potential glycemic memory response. To understand the long-term effects of these changes, we also performed sham or transverse aortic constriction (TAC) surgery at this four-week timepoint to induce pressure overload-mediated secondary stress. Mice were then followed for an additional 8 weeks and assessed for contractile function by echocardiography, cellular remodeling, and molecular analysis. Pressure overload led to an exacerbated hypertrophic response and cardiac dysfunction. Subsequent qPCR-mediated expression analysis identified molecular changes akin to heart failure, worsened cardiac fibrosis, and impaired oxidative stress. CONCLUSIONS: These results indicate an altered transcriptome and DNA methylome upon prior transient enhanced glucose delivery, which evokes a glycemic memory response, responsible for long-term heart failure predisposition. We also identified molecular signatures of differential expression and methylation, as well as potential hubs that may provide novel targets for mechanistic understanding and therapeutic interventions.

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Persistent Methylmalonate Overload Despite Glycemic Control Drives Mitochondrial Dyshomeostasis and Subclinical Heart Damage in Diabetes

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