MK2 deficiency decreases mortality during the inflammatory phase after myocardial infarction in mice

Trepanier, J.; Nawaito, S. A.; Sahadevan, P.; Sahmi, F.; Duquette, N.; Gelinas, D.; Gillis, M.-A.; Shi, Y.; Torok, C.; Clavet-Lanthier, M.-E.; Gaestel, M.; Sirois, M. G.; Tardif, J.-C.; Allen, B. G.

doi:10.1101/2023.03.06.531384

bioRxiv · 10.1101/2023.03.06.531384

MK2 deficiency decreases mortality during the inflammatory phase after myocardial infarction in mice

Trepanier, J.·Nawaito, S. A.·Sahadevan, P.·Sahmi, F.·Duquette, N.·Gelinas, D.·Gillis, M.-A.·Shi, Y.·Torok, C.·Clavet-Lanthier, M.-E.·Gaestel, M.·Sirois, M. G.·Tardif, J.-C.·Allen, B. G.

View original source ↗Export metadata ↓

Abstract

BackgroundAltering the onset, intensity, or duration of inflammation can impact the recovering hearts structure and function following myocardial infarction (MI). Substrates of MAP kinase-activated protein kinase 2 (MK2) include proteins that regulate the stability of AU-rich transcripts, including those of several pro-inflammatory cytokines. This study was to determine if MK2-deficiency impaired the inflammatory phase of post-MI wound repair. Methods and ResultsMyocardial infarctions were induced by permanent ligation of the left anterior descending coronary artery in 12-week-old male MK2+/+ and MK2-/- littermate mice. Five days post-MI, survival was 100% in MI-MK2-/- (n = 20) and 79% in MI-MK2+/+ mice (n = 29; Mandel-Cox test: P < 0.05). Area at risk and infarct size were similar. Echocardiographic imaging revealed that both systolic and diastolic LV diameters were greater in MI-MK2+/+ than MI-MK2-/- mice. MK2-deficiency did not affect the increase in wall motion score index. Infiltration of neutrophils or monocytes did not differ significantly. Cytokine and chemokine transcripts were quantified in infarcted and non-infarcted LV tissue using qPCR arrays (QIAGEN). Three days post-MI, Ifna2 was increased and Il16 was decreased in infarcted tissue from MK2-/- hearts, compared with infarcted MK2+/+ tissue, whereas in the non-infarcted MK2-/- myocardium Il27 increased and Tnfsf11, Ccl3, and Il1rn were decreased. Five days post-MI, Ctf16 and Il10 increased in infarcted MK2-/- tissue whereas in the non-infarcted MK2-/- myocardium Ccl9, Nodal, and Xcl2 increased and Il15 decreased. ConclusionsThe findings of this study suggest MK2-deficiency is an advantage during the inflammatory phase of cardiac wound repair post-MI. Clinical PerspectiveWhat is new? -The effects of MAP kinase-activated protein kinase 2 (MK2) deficiency on survival, cardiac structure and function, and the inflammatory phase of wound healing following myocardial infarction were assessed using a constitutive, pan MK2-null mouse model. -MK2-deficiency reduced mortality but did not alter area at risk or infarct size post-myocardial infarction. Inflammatory cell infiltration was also unaffected. -MK2-deficiency altered the abundance of several cytokines (increased, decreased) in infarcted and non-infarcted myocardium post-MI. What are the clinical implications? -The initial phase of wound repair post-MI involves inflammation. -The risk of damage to the myocardium and mortality may be reduced by inhibition of MK2 activity during the inflammatory phase of wound healing post-MI.

Explore related subjects

physiology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Trepanier, J., Nawaito, S. A., Sahadevan, P., Sahmi, F., Duquette, N., Gelinas, D., Gillis, M.-A., Shi, Y., Torok, C., Clavet-Lanthier, M.-E., Gaestel, M., Sirois, M. G., Tardif, J.-C., Allen, B. G.. 2023-03-08. MK2 deficiency decreases mortality during the inflammatory phase after myocardial infarction in mice. https://doi.org/10.1101/2023.03.06.531384

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Rad and Phospholamban are Key Drivers of the Ventricular Adrenergic Response and Stress-Induced Arrhythmia

The adrenergic response is a fundamental mechanism that regulates heart rate (chronotropy), cardiac contractility (inotropy) and relaxation (lusitropy). Adrenergic stress is also a recognized trigger of arrhythmia in disease. Yet, our understanding of the underlying molecular basis remains incomplete. Protein kinase A (PKA) and the calcium/calmodulin-dependent kinase II (CaMKII) phosphorylate multiple targets proposed to participate in the adrenergic response, including the GTP-binding protein Rad, phospholamban (PLB) and ryanodine receptor 2 (RyR2). Here we demonstrate that phosphorylation of both Rad and PLB is necessary for inotropy and lusitropy. We show that changes in cardiac contractility and relaxation are primarily dependent on intracellular calcium handling. Finally, we report that Rad and PLB control stress-induced arrhythmogenesis, despite the phosphorylation of other pro-arrhythmic targets. We have identified the essential molecular components of the adrenergic response, resolving a long-standing debate in cardiac excitation-contraction coupling and refining current models of sympathetic regulation in health and disease.

physiology↗

bioRxiv2026

MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss

Metabolites are increasingly recognized as circulating molecules that regulate physiology, yet the mechanisms that couple intracellular production to organism-wide action remain poorly defined. Using the anorexigenic metabolite Lac-Phe as a tractable system, we identify the orphan transporter MCT6 (SLC16A5) as a physiologic intestinal Lac-Phe exporter. This mechanism controls the extent to which intracellularly synthesized Lac-Phe acquires systemic activity. MCT6 transports Lac-Phe, mediates its cellular efflux, and is required for maintaining its blood levels in mice following strong glycolytic stimuli. Both global and intestinal epithelial-specific deletion of MCT6 confers resistance to metformin-associated weight loss on a high-fat diet. Bypassing the transport defect with exogenous Lac-Phe normalizes the body weight phenotype of MCT6-KO mice. Together, these data connect MCT6 to metformin pharmacology and intestinal lactate metabolism, and more generally underscore the importance of transporter-mediated release in the conversion of an intracellular metabolic state into a circulating metabolite effector.

physiology↗

bioRxiv2026

DEPP1 connects nutrient and oxygen availability to maintenance of muscle mass

Nutrients and oxygen are sensed within the muscle to control growth and disruption of either signal is sufficient to lead to muscle atrophy. While nutrient limitation is sensed via a conserved transcriptional atrophy program (commonly referred to as atrogenes) dictated via the Forkhead box O (FoxO) transcription factors, how low oxygen promotes muscle loss remains unknown. Accordingly, the downstream mechanisms that initiate muscle loss when oxygen and nutrients are limiting are only partly understood. Here, we find Hypoxia Inducible Factor (HIF), the master regulator of our adaptation to low oxygen, is necessary and sufficient to mediate muscle loss under hypoxia in mice. RNA sequencing in skeletal muscle isolated from starved or hypoxic mice identifies Decidual Protein Induced by Progesterone 1 (Depp1), which is induced in skeletal muscle when nutrients or oxygen is limiting via FoxO1 and HIF activation, respectively. Whole body Depp1 loss in mice reduces muscle loss under fasting and hypoxia and skeletal muscle Depp1 overexpression is sufficient to mediate muscle atrophy. Mechanistically, Depp1 localizes to the mitochondria and is necessary to control autophagy activation and mitochondrial degradation in skeletal muscle. Taken together, our studies nominate Depp1 as a new atrogene necessary for muscle loss under multiple atrophy scenarios involving FoxO and HIF.

physiology↗