Loss of SM-B myosin affects muscle shortening velocity and maximal force development

Babu, Gopal J.; Loukianov, Evgeny; Loukianova, Tatiana; Pyne, Gail J.; Huke, Sabine; Osol, George; Low, Robert B.; Rutgeerts, Paul; Periasamy, Muthu

doi:10.1038/ncb1101-1025

Cited by 81 publications

(109 citation statements)

References 27 publications

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“…We speculate that as in vascular SMCs, the gross alterations in visceral tissues are, at least in part, attributable to the loss of SRF/myocardinactivated SMC contractile genes. In support of this model, MYH11-deficient mice demonstrated vascular complications as well as dysfunction of bladder and intestine (18,19). Moreover, de novo mutations in ACTA2 causes multisystem smooth muscle dysfunction that includes aortic and cerebrovascular disease, fixed dilated pupils, hypotonic bladder, malrotation, and hypoperistalsis of the gut (20).…”

Section: Discussionmentioning

confidence: 99%

Myocardin is required for maintenance of vascular and visceral smooth muscle homeostasis during postnatal development

Huang

Wang

Wright³

et al. 2015

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

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Myocardin is a muscle-restricted transcriptional coactivator that activates a serum response factor (SRF)-dependent gene program required for cardiogenesis and embryonic survival. To identify myocardin-dependent functions in smooth muscle cells (SMCs) during postnatal development, mice harboring a SMC-restricted conditional, inducible Myocd null mutation were generated and characterized. Tamoxifen-treated SMMHC-Cre ERT2 /Myocd F/F conditional mutant mice die within 6 mo of Myocd gene deletion, exhibiting profound derangements in the structure of great arteries as well as the gastrointestinal and genitourinary tracts. Conditional mutant mice develop arterial aneurysms, dissection, and rupture, recapitulating pathology observed in heritable forms of thoracic aortic aneurysm and dissection (TAAD). SMCs populating arteries of Myocd conditional mutant mice modulate their phenotype by down-regulation of SMC contractile genes and up-regulation of extracellular matrix proteins. Surprisingly, this is accompanied by SMC autonomous activation of endoplasmic reticulum (ER) stress and autophagy, which over time progress to programmed cell death. Consistent with these observations, Myocd conditional mutant mice develop remarkable dilation of the stomach, small intestine, bladder, and ureters attributable to the loss of visceral SMCs disrupting the muscularis mucosa. Taken together, these data demonstrate that during postnatal development, myocardin plays a unique, and important, role required for maintenance and homeostasis of the vasculature, gastrointestinal, and genitourinary tracts. The loss of myocardin in SMCs triggers ER stress and autophagy, which transitions to apoptosis, revealing evolutionary conservation of myocardin function in SMCs and cardiomyocytes. Mice harboring a null mutation in the myocardin gene (Myocd) exhibit a block in cardiomyocyte proliferation accompanied by a dramatic increase in cardiomyocyte apoptosis, leading to lethality at midgestation (5). Ablation of Myocd in the adult heart leads to heart failure and lethality attributable to a disruption in sarcomere structure accompanied by programmed cell death (6). By contrast, mice harboring a neural crest-restricted ablation of Myocd die in the perinatal period from patent ductus arteriosus (PDA) attributable to a block in the SMC contractile gene program (7).After more than a decade of study, fundamental questions regarding the function of myocardin in vascular SMCs during postnatal development as well as visceral SMCs populating the gastrointestinal and genitourinary tracts remain unanswered. Is myocardin required for SMC contractile gene expression and maintenance of arterial tone? What role, if any, does myocardin play in regulating expression of SRF-regulated SMC contractile genes in visceral SMCs? Do the related transcriptional coactivators MKL-1 and/or MKL-2 mediate redundant functions with myocardin in the adult vasculature or visceral tissues (4)? Is myocardin required for survival of vascular SMCs in a manner analogous to that it plays in c...

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Section: Discussionmentioning

confidence: 99%

Myocardin is required for maintenance of vascular and visceral smooth muscle homeostasis during postnatal development

Huang

Wang

Wright³

et al. 2015

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

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“…Protein expression was analyzed by western blotting as described elsewhere (Babu et al, 2001). Briefly, crude myofibrillar proteins isolated from bladder were separated by electrophoresis on SDS-PAGE (5% for SM2 and SM1; 10% for -actin and tropomyosin), and transferred to a nitrocellulose membrane.…”

Section: Analyses Of Protein Expressionmentioning

confidence: 99%

SM2+/- male mice are predisposed to develop urinary tract obstruction and hyper contractility of the bladder smooth muscle upon ageing

Chi

Zhou

Sopariwala

et al. 2011

J. Smooth Muscle Res.

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We previously showed that complete loss of smooth muscle myosin heavy chain isoform 2 (SM2) resulted in postnatal lethality, but in het mice a partial loss of SM2 (SM2 +/-) was accompanied by down-regulation of SM1 with unaltered SM2:SM1 ratio. To determine whether a normal bladder function would be maintained throughout its lifespan, we aged WT and SM2 +/-mice up to 18 months and analyzed a) SM2:SM1 ratio b) bladder smooth muscle structure and c) function in SM2 +/-het mice. A notable finding was that ~50% of 15-18 months old male SM2 +/-mice exhibited urinary retention in bladder with the distention of upper urethra. In SM2 +/-mouse bladder with urinary retention, the SM2:SM1 ratio was decreased but not in SM2 +/-mouse bladder that did not develop urinary retention. Interestingly in the distended bladder the expression levels of -actin and tropomyosin remained unaltered despite a reduction in the number of myosin thick filaments. These distended bladders showed hypersensitivity to submaximal K + depolarization and M3-receptor stimulation, without a significant increase in myosin light chain phosphorylation. We therefore suggest that a partial loss of SM2 may predispose male mice to develop lower urinary tract obstruction during ageing. In addition our data suggest that bladder obstruction can cause a further reduction in SM2 expression and SM2:SM1 ratio, and a hyper-contractility of the bladder smooth muscle.

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“…The acidic isoform (LC 17a ) is coexpressed with the plus-insert heavy chain whereas the basic isoform (LC 17b ) coexpresses with the minus-insert heavy chain (17)(18)(19). Based on in vitro motility studies, the presence or absence of the sevenamino acid insert in the heavy chain is the sole determinant of the 2-fold faster actin filament velocities for the plus-insert myosin compared with the minus-insert myosin (14,20,21), which in part may contribute to the differences in shortening velocity for phasic and tonic smooth muscles (22,23). The absence of the seven-amino acid insert, in addition to the presence of the LC 17b isoform that is coexpressed with the minusinsert heavy chain (24), may be responsible for the unique ability of the tonic muscle to enter a latch state (25) in which high contractile forces are maintained with minimal expenditure of chemical energy (i.e.…”

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confidence: 99%

The Unique Properties of Tonic Smooth Muscle Emerge from Intrinsic as Well as Intermolecular Behaviors of Myosin Molecules

Baker

Brosseau

Fagnant

et al. 2003

Journal of Biological Chemistry

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To better understand the molecular basis for some of the unique mechanical properties of tonic smooth muscle, we use a laser trap to assay the mechanochemistry of single smooth muscle heavy meromyosin molecules lacking a seven-amino acid insert in the nucleotide binding loop (minus insert). We measured a second-order ATP-induced actin dissociation rate, k T , of 2. , and an ADP affinity, K D , of 3.2 M, which is more than 100-fold greater than that measured for skeletal muscle myosin. By performing in vitro motility studies under nearly identical conditions, we show that the relatively slow actin velocity generated by minus-insert heavy meromyosin is significantly influenced, but not limited, by k ؊D . Our results support a model in which two separate intermediate steps in the actin-myosin catalyzed ATP hydrolysis reaction are energetically coupled through mechanical interactions, and we discuss this model in the context of the ability of tonic muscle to maintain high forces at low energetic cost (latch).Muscle shortening and force generation result from actinmyosin binding events that are coupled to the actin-myosin catalyzed ATP hydrolysis reaction illustrated in Fig. 1. Upon binding to an actin filament (A) and releasing inorganic phosphate (P i ), myosin undergoes a large and discrete rotation of its lever-like light chain domain, which is capable of generating both motion and force (1-5). With the subsequent release of ADP (at the rate k ϪD ) an additional rotation of the light chain domain of myosin has been observed in smooth muscle myosin (6, 7), but unlike the work generating rotation associated with actin binding/P i release, the rotation associated with ADP release is thought to be a strain-sensing biochemical step (8 -10). Following the release of ADP, ATP binding induces the detachment of myosin from the actin filament (at the rate k T ), after which ATP is hydrolyzed.Muscles differ significantly in their shortening speeds and force-generating capacities. For instance, smooth muscle produces a greater average force per myosin and slower speeds of shortening than skeletal muscle (11). To a large extent these mechanical differences are caused by kinetic differences among the different myosin isoforms that exist within different muscle types (12, 13). For example, phasic and tonic smooth muscle (found in the intestine and aorta respectively) express two myosin heavy chain isoforms that differ by a seven-amino acid insert in a surface loop spanning their nucleotide binding pocket (14 -16). Phasic smooth muscle contains primarily the plus-insert myosin, whereas tonic smooth muscle contains primarily the minus-insert myosin. In addition, two essential light chain isoforms are coordinately expressed with the heavy chain isoforms. The acidic isoform (LC 17a ) is coexpressed with the plus-insert heavy chain whereas the basic isoform (LC 17b ) coexpresses with the minus-insert heavy chain (17-19). Based on in vitro motility studies, the presence or absence of the sevenamino acid insert in the heavy chain is t...

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Loss of SM-B myosin affects muscle shortening velocity and maximal force development

Cited by 81 publications

References 27 publications

Myocardin is required for maintenance of vascular and visceral smooth muscle homeostasis during postnatal development

Myocardin is required for maintenance of vascular and visceral smooth muscle homeostasis during postnatal development

SM2+/- male mice are predisposed to develop urinary tract obstruction and hyper contractility of the bladder smooth muscle upon ageing

The Unique Properties of Tonic Smooth Muscle Emerge from Intrinsic as Well as Intermolecular Behaviors of Myosin Molecules

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