Signaling to Myosin Regulatory Light Chain in Sarcomeres

Kamm, Kristine E.; Stull, James T.

doi:10.1074/jbc.r110.198697

Cited by 101 publications

(112 citation statements)

References 96 publications

(126 reference statements)

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“…Importantly, our findings imply that the reduction in peak force induced by SA is mainly related to MyHC-2B, SERCA1, MLCK2, and MLC2 expression. These proteins are highly expressed in fast-twitch muscles, and they play a pivotal role in muscle force potentiation (25,26). In accordance, we found that peak force, MyHC-2B mRNA/protein and MLCK2 mRNA levels were preserved in mKO OVL, whereas MLC2 protein levels were even increased.…”

Section: Discussionsupporting

confidence: 80%

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The transcriptional coactivator PGC-1α is dispensable for chronic overload-induced skeletal muscle hypertrophy and metabolic remodeling

Pérez-Schindler

Summermatter

Santos

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Skeletal muscle mass loss and dysfunction have been linked to many diseases. Conversely, resistance exercise, mainly by activating mammalian target of rapamycin complex 1 (mTORC1), promotes skeletal muscle hypertrophy and exerts several therapeutic effects. Moreover, mTORC1, along with peroxisome proliferatoractivated receptor γ coactivator 1α (PGC-1α), regulates skeletal muscle metabolism. However, it is unclear whether PGC-1α is required for skeletal muscle adaptations after overload. Here we show that although chronic overload of skeletal muscle via synergist ablation (SA) strongly induces hypertrophy and a switch toward a slow-contractile phenotype, these effects were independent of PGC-1α. In fact, SA down-regulated PGC-1α expression and led to a repression of energy metabolism. Interestingly, however, PGC-1α deletion preserved peak force after SA. Taken together, our data suggest that PGC-1α is not involved in skeletal muscle remodeling induced by SA.muscle overload | transcriptional regulation | resistance training S keletal muscle size exhibits drastic changes throughout life, mainly dependent on mechanical load and nutritional supply (1). For example, loss of muscle mass is observed during immobilization and starvation, but also under pathological conditions like heart failure and cancer (2). To date, resistance exercise is considered as one of the most efficient ways to induce skeletal muscle hypertrophy and to revert the adverse effects of muscle wasting (2, 3). However, because pharmacological interventions are scarce, identification of the molecular regulation of muscle remodeling via resistance exercise is of great therapeutic interest.Activation of mammalian target of rapamycin complex 1 (mTORC1) is the main regulatory step by which resistance exercise enhances protein synthesis and skeletal muscle size (4). In fact, inhibition of mTORC1 drastically abrogates plantaris hypertrophy via chronic overload (5), even though muscle size is not affected uniformly by muscle knockout of the mTORC1 inhibitor tuberous sclerosis complex 1 (6). Interestingly, the activity of the mTORC1 protein kinase complex positively correlates with oxidative capacity (7,8). Moreover, mTORC1 is recruited to the promoter of a wide range of metabolism-related genes to regulate their expression (9-11). In skeletal muscle, mTORC1 regulates oxidative metabolism by facilitating the activation of Yin Yang 1 by the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) (10, 12). The physiological context in which the mTORC1-PGC-1α axis regulates energy metabolism, however, is unknown.Protein degradation is an important limiting factor of skeletal muscle hypertrophy. This process is fine-tuned by the transcription factor forkhead box O3 (FOXO3), which regulates the expression of the E3 ubiquitin ligases muscle ring finger protein 1 (MuRF1) and F-box protein 32 (Fbxo32/atrogin-1) (13). Interestingly, PGC-1α represses FOXO3 activity and consequently ameliorates skeletal muscle mass loss during denervation and aging (14-16)...

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Section: Discussionsupporting

confidence: 80%

“…S3A). We finally analyzed myosin regulatory light chain (MLC) phosphorylation by MLC kinase 2 (MLCK2), a key process for the potentiation of force generation (26). MLCK2 mRNA content decreased by ∼42% in mTg CON and WT OVL (Fig.…”

Section: Significancementioning

confidence: 99%

The transcriptional coactivator PGC-1α is dispensable for chronic overload-induced skeletal muscle hypertrophy and metabolic remodeling

Pérez-Schindler

Summermatter

Santos

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…It is localized at the headrod junction of the myosin heavy chain (MHC), and, in addition to the N-terminal Ca 2+ -Mg 2+ binding site, it also contains the myosin light chain kinase (MLCK)-specific phosphorylatable Serine15. Phosphorylation of Ser15 has been recognized to play an important role in cardiac muscle contraction under normal and disease conditions (9). Significantly reduced RLC phosphorylation was reported in patients with heart failure (10, 11) and observed in animal models of cardiac disease (5, [12][13][14].…”

mentioning

confidence: 99%

Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice

Yuan

Muthu

Kazmierczak

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

127

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Myosin light chain kinase (MLCK)-dependent phosphorylation of the regulatory light chain (RLC) of cardiac myosin is known to play a beneficial role in heart disease, but the idea of a phosphorylation-mediated reversal of a hypertrophic cardiomyopathy (HCM) phenotype is novel. Our previous studies on transgenic (Tg) HCM-RLC mice revealed that the D166V (Aspartate166 →Valine) mutation-induced changes in heart morphology and function coincided with largely reduced RLC phosphorylation in situ. We hypothesized that the introduction of a constitutively phosphorylated Serine15 (S15D) into the hearts of D166V mice would prevent the development of a deleterious HCM phenotype. In support of this notion, MLCK-induced phosphorylation of D166V-mutated hearts was found to rescue some of their abnormal contractile properties. Tg-S15D-D166V mice were generated with the human cardiac RLC-S15D-D166V construct substituted for mouse cardiac RLC and were subjected to functional, structural, and morphological assessments. The results were compared with Tg-WT and Tg-D166V mice expressing the human ventricular RLC-WT or its D166V mutant, respectively. Echocardiography and invasive hemodynamic studies demonstrated significant improvements of intact heart function in S15D-D166V mice compared with D166V, with the systolic and diastolic indices reaching those monitored in WT mice. A largely reduced maximal tension and abnormally high myofilament Ca 2+ sensitivity observed in D166V-mutated hearts were reversed in S15D-D166V mice. Lowangle X-ray diffraction study revealed that altered myofilament structures present in HCM-D166V mice were mitigated in S15D-D166V rescue mice. Our collective results suggest that expression of pseudophosphorylated RLC in the hearts of HCM mice is sufficient to prevent the development of the pathological HCM phenotype.cardiomyopathy | hemodynamics | myocardial contraction | X-ray structure | myosin RLC

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“…This claim of a spatial gradient of RLC phosphorylation, however, has been challenged by the Stull group and quantitative measurements have revealed no evidence for its existence in the hearts of WT and transgenic mice overexpressing cMLCK (Huang et al 2008;Kamm and Stull 2011). Significantly depressed Ser-15 RLC phosphorylation was reported in HF patients (van der Velden et al 2003a, b) and was also observed in experimental animal models of cardiac disease (Scruggs et al 2009;Sheikh et al 2012;Yuan et al 2015).…”

Section: Genetic Mutations In Myosin Regulatory Light Chain Lead To Cmentioning

confidence: 99%

“…1). In the beating heart under basal physiological conditions, RLC was seen to be phosphorylated at about 0.4 mol of phosphate (Pi)/mol of RLC in a variety of animal species, including humans (Huang et al 2008;Kamm and Stull 2011). More recently, rodent hearts were shown to be basally phosphorylated at less than 0.05 mol Pi/mol RLC in vivo (Kampourakis and Irving 2015), creating an absence of a clear consensus.…”

Section: Introductionmentioning

confidence: 99%

Pseudophosphorylation of cardiac myosin regulatory light chain: a promising new tool for treatment of cardiomyopathy

Yadav

Szczesna‐Cordary

2017

Biophys Rev

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Many genetic mutations in sarcomeric proteins, including the cardiac myosin regulatory light chain (RLC) encoded by the MYL2 gene, have been implicated in familial cardiomyopathies. Yet, the molecular mechanisms by which these mutant proteins regulate cardiac muscle mechanics in health and disease remain poorly understood. Evidence has been accumulating that RLC phosphorylation has an influential role in striated muscle contraction and, in addition to the conventional modulation via Ca 2+ binding to troponin C, it can regulate cardiac muscle function. In this review, we focus on RLC mutations that have been reported to cause cardiomyopathy phenotypes via compromised RLC phosphorylation and elaborate on pseudo-phosphorylation rescue mechanisms. This new methodology has been discussed as an emerging exploratory tool to understand the role of phosphorylation as well as a genetic modality to prevent/rescue cardiomyopathy phenotypes. Finally, we summarize structural effects postphosphorylation, a phenomenon that leads to an ordered shift in the myosin S1 and RLC conformational equilibrium between two distinct states.

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Signaling to Myosin Regulatory Light Chain in Sarcomeres

Cited by 101 publications

References 96 publications

The transcriptional coactivator PGC-1α is dispensable for chronic overload-induced skeletal muscle hypertrophy and metabolic remodeling

The transcriptional coactivator PGC-1α is dispensable for chronic overload-induced skeletal muscle hypertrophy and metabolic remodeling

Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice

Pseudophosphorylation of cardiac myosin regulatory light chain: a promising new tool for treatment of cardiomyopathy

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