Mitogen-Activated Protein Kinase-Activated Protein Kinases 2 and 3 Regulate SERCA2a Expression and Fiber Type Composition To Modulate Skeletal Muscle and Cardiomyocyte Function

Scharf, Madeleine; Neef, Stefan; Freund, Robert; Geers-Knörr, Cornelia; Franz‐Wachtel, Mirita; Brandis, Almuth; Krone, Dorothee; Schneider, Heike; Groos, Stephanie; Menon, Manoj B.; Chang, Kin-Chow; Kraft, Theresia; Meißner, J.; Boheler, Kenneth R.; Maier, Lars S.; Gaestel, Matthias; Scheibe, Renate

doi:10.1128/mcb.01692-12

Cited by 46 publications

(49 citation statements)

References 83 publications

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“…Several transcriptional factors have been implicated in the regulation of SERCA2a transcription in HF3738. Among these, transcription factor Sp1 is critical in the regulation of SERCA2a gene expression39. Sp1 is a ubiquitously expressed transcription factor involved in the regulation of a large number of genes including housekeeping genes as well as actively regulated genes.…”

Section: Discussionmentioning

confidence: 99%

Luteolin improves cardiac dysfunction in heart failure rats by regulating sarcoplasmic reticulum Ca2+-ATPase 2a

et al. 2017

Sci Rep

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We previously found that luteolin (Lut) appeared to improve the contractility of cardiomyocytes during ischemia/reperfusion in rats. The enhancement was associated with the alteration in sarcoplasmic reticulum Ca 2+ -ATPase 2a (SERCA2a). This finding prompted us to consider if the mechanism worked in heart failure (HF). We studied the regulation of SERCA2a by Lut in failing cardiomyocytes and intact heart of rats. Improvement of contractility and the mechanisms centered on SERCA2a were studied in isolated cardiomyocytes and intact heart. We found that Lut significantly improved contractility and Ca 2+ transients, ameliorated expression, activity and stability of SERCA2a and upregulated expression of small ubiquitin-related modifier (SUMO) 1, which is a newfound SERCA2a regulator. Lut also increased phosphorylation of protein kinase B (Akt), phospholaban (PLB) and sumoylation of SERCA2a, specificity protein 1 (Sp1). Transcriptions of SUMO1 and SERCA2a were concurrently increased. Inhibition of posphatidylinositol 3 kinase/Akt (PI3K/Akt) pathway and SERCA2a activity both markedly abolished Lut-induced benefits in vitro and in vivo. Lut upregulated the expression ratio of Bcl-2/Bax, caspase-3/cleaved-Caspase3. Meanwhile, Lut ameliorated the myocardium fibrosis of HF. These discoveries provide an important potential therapeutic strategy that Lut targeted SERCA2a SUMOylation related to PI3K/Akt-mediated regulations on rescuing the dysfunction of HF.Heart failure (HF) is a complex syndrome that results from the deterioration of the cardiac structure and function, characterized by the impaired ability of the ventricle to fill with or eject blood 1 . It is an ultimate common pathway that begins with diverse etiologies, such as hypertension, ischemia, tachycardia, infection, metabolic disorder, and cardiomyopathy, and develops with continual activation of the renin-angiotensin and sympathetic nervous systems. The incidence, prevalence and economic burden of HF are now steadily increasing due to the aging of the population and transition of acute cardiac problems into chronic disorders.Abnormality Ca 2+ homeostasis is a universal characteristic of human and experimental HF 2 . Ca 2+ homeostasis is directly modulated by four proteins: L-type Ca 2+ channel and Na + /Ca 2+ exchanger (NCX) in cell membrane, Ca 2+ -ATPase and ryanodine receptor type 2 in sarcoplasmic reticulum (SR) 3 . Any abnormality of the expression or activity of the Ca 2+ handling proteins mentioned above leads to alterations in cardiac contractility. Sarcoplasmic reticulum Ca 2+ -ATPase 2a (SERCA2a), a principal cardiac form of SERCA, is important in controlling excitation/contraction coupling. SERCA2a's role in HF has been extensively studied in animal models and human, which have shown that SERCA expression and activity are reduced in failing myocardium 4 . Genetic treatments show that reduction in SERCA2a level results in impaired intracellular Ca 2+ homeostasis and reduces both systolic and diastolic function 5,6 . These results indicate that modul...

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Section: Discussionmentioning

confidence: 99%

Luteolin improves cardiac dysfunction in heart failure rats by regulating sarcoplasmic reticulum Ca2+-ATPase 2a

et al. 2017

Sci Rep

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“…Importantly, protein modifications not only regulate the activities of PGC-1s but also adjust them according to specific gene programs by regulating their interactions with specific transcriptional regulators. For example, PGC-1α can be phosphorylated directly by AMPK and p38 mitogen-activated protein kinase (MAPK), which further stimulate its transactivation activity and inhibit its degradation (Gundewar et al, 2009;Scharf et al, 2013;. AMPK also facilitates the activation of silent information regulator 1 (SIRT1), which further increases PGC-1α transcriptional activity (Canto et al, 2009;Jiang et al, 2017;Liang et al, 2017).…”

Section: Regulation Of Pgc-1mentioning

confidence: 99%

PGC-1: The Energetic Regulator in Cardiac Metabolism

Di¹,

Lv²,

Jiang³

et al. 2018

Current Issues in Molecular Biology

105

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The peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1s (PGC-1s) can induce the expression of several downstream genes that play pivotal roles in the regulation of mitochondrial biogenesis and metabolism in the heart. Moreover, PGC-1 signaling pathways have also been reported to play a critical role in cardioprotection. Given the significance of PGC-1 coactivators, we summarize the current literature on the molecular mechanisms and roles of PGC-1s in cardiac metabolism. Thus, in this review, we first introduce the basic knowledge regarding PGC-1 signaling pathways. We then discuss their roles in heart metabolism. Moreover, we describe several significant treatments that target the PGC-1 signaling pathway. This review presents the significant roles of PGC-1s in cardiac metabolism and may contribute to the promotion of PGC-1 signaling pathway as a novel therapeutic target.

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“…In heart, p38 MAPK and MAPKAPK2/3 are highly abundant, and chronic p38 MAPK activation is involved in cardiac pathologies . In addition, MAPKAPK2/3‐deficiency increased contractile activity in cardiomyocytes . Therefore, we investigated possible effects of MuRF2 and MuRF3 ‐deficiency in soleus muscle and left ventricle on MAPKAPK2/3 protein levels and a potential interaction of MuRF2 and MuRF3 with MAPKAPK2/3.…”

Section: Introductionmentioning

confidence: 99%

Muscle RING-finger 2 and 3 maintain striated-muscle structure and function

Lodka

Pahuja

Geers-Knörr

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

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BackgroundThe Muscle‐specific RING‐finger (MuRF) protein family of E3 ubiquitin ligases is important for maintenance of muscular structure and function. MuRF proteins mediate adaptation of striated muscles to stress. MuRF2 and MuRF3 bind to microtubules and are implicated in sarcomere formation with noticeable functional redundancy. However, if this redundancy is important for muscle function in vivo is unknown. Our objective was to investigate cooperative function of MuRF2 and MuRF3 in the skeletal muscle and the heart in vivo.Methods MuRF2 and MuRF3 double knockout mice (DKO) were generated and phenotypically characterized. Skeletal muscle and the heart were investigated by morphological measurements, histological analyses, electron microscopy, immunoblotting, and real‐time PCR. Isolated muscles were subjected to in vitro force measurements. Cardiac function was determined by echocardiography and working heart preparations. Function of cardiomyocytes was measured in vitro. Cell culture experiments and mass‐spectrometry were used for mechanistic analyses.ResultsDKO mice showed a protein aggregate myopathy in skeletal muscle. Maximal force development was reduced in DKO soleus and extensor digitorum longus. Additionally, a fibre type shift towards slow/type I fibres occurred in DKO soleus and extensor digitorum longus. MuRF2 and MuRF3‐deficient hearts showed decreased systolic and diastolic function. Further analyses revealed an increased expression of the myosin heavy chain isoform beta/slow and disturbed calcium handling as potential causes for the phenotype in DKO hearts.ConclusionsThe redundant function of MuRF2 and MuRF3 is important for maintenance of skeletal muscle and cardiac structure and function in vivo.

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Mitogen-Activated Protein Kinase-Activated Protein Kinases 2 and 3 Regulate SERCA2a Expression and Fiber Type Composition To Modulate Skeletal Muscle and Cardiomyocyte Function

Cited by 46 publications

References 83 publications

Luteolin improves cardiac dysfunction in heart failure rats by regulating sarcoplasmic reticulum Ca2+-ATPase 2a

Luteolin improves cardiac dysfunction in heart failure rats by regulating sarcoplasmic reticulum Ca2+-ATPase 2a

PGC-1: The Energetic Regulator in Cardiac Metabolism

Muscle RING-finger 2 and 3 maintain striated-muscle structure and function

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