Differential effects of ovariectomy on calcium activation of cardiac and soleus myofilaments

Wattanapermpool, Jonggonnee; Reiser, Peter J.

doi:10.1152/ajpheart.1999.277.2.h467

Cited by 67 publications

(81 citation statements)

References 28 publications

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“…Specifically, F sex was associated with a lower myofilament sensitivity to Ca 2ϩ activation (Fig. 3A), consistent with previous reports of enhanced myofilament Ca 2ϩ sensitivity in overectomized F rats (4,46,52). F sex was also associated with a higher V slack , as measured by the slack test (Fig.…”

Section: Discussionsupporting

confidence: 90%

“…Gonadectomy in rats of either sex leads to a significantly reduced myosin ATPase consistent with the concomitant ϳ30 -40% reduction in ␣-MHC (3,38,39,52). Testosterone recovers cardiac function in gonectomized rats of either sex (39), whereas estrogen reduces myofilament sensitivity to Ca 2ϩ activation (4,46,52). Collectively, these observations imply that the sarcomeric incorporation of a differently performing myosin, such as the R403Q mutant ␣MHC, would modify myofilament performance and, in addition, in a sex-dependent manner.…”

mentioning

confidence: 64%

“…It has already been observed that cardiac contractile function and contractile reserve are enhanced in male compared with female animals (34,38,39). Gonadectomy in rats of either sex leads to a significantly reduced myosin ATPase consistent with the concomitant ϳ30 -40% reduction in ␣-MHC (3,38,39,52). Testosterone recovers cardiac function in gonectomized rats of either sex (39), whereas estrogen reduces myofilament sensitivity to Ca 2ϩ activation (4,46,52).…”

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Myofilament mechanical performance is enhanced by R403Q myosin in mouse myocardium independent of sex

Palmer¹,

Wang²,

Teekakirikul³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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, respectively) develop significant hypertrophic cardiomyopathy (HCM) compared with male and female wild-type mice (M-␣MHC ϩ/ϩ and F-␣MHC ϩ/ϩ , respectively) after ϳ30 wk of age. We tested the hypothesis that myofilament mechanical performance differs between M-␣MHC R403Q/ϩ and F-␣MHC R403Q/ϩ at younger ages (10 -20 wk) and could account for sex differences in HCM development. The sensitivity of chemically skinned myocardial strips to Ca 2ϩ activation (pCa50) was significantly (P Ͻ 0.05) enhanced in male mice independent of genotype (M-␣MHC Ϫ3 , F-␣MHC ϩ/ϩ 25 Ϯ 3 10 Ϫ3 muscle lengths/s ϫ normalized tension). We did not find a statistically significant sex ϫ mutation interaction for any measure of myofilament performance. Therefore, sarcomeric incorporation of the R403Q myosin similarly enhanced left ventricular myofilament mechanical performance in both male and female mice. The sex-dependent development of HCM due to the R403Q myosin may then be inhibited by female sex hormones, which may additionally underlie the observed sex differences for pCa50 and unloaded shortening velocity. hypertrophic cardiomyopathy; myosin heavy chain; isometric tension; calcium sensitivity; force-velocity HYPERTROPHIC CARDIOMYOPATHY (HCM) in the absence of recognizable hemodynamic risk factors can arise naturally as a consequence of a mutant allele for myosin heavy chain (MHC) (41). Assessing the functional consequences of HCM-associated mutations, such as the R403Q point mutation in cardiac ␣-MHC or ␤-MHC, has played an important role in the identification of modifications in myofilament performance that may lead to the HCM phenotype (9,19,36,51). However, functional data from some models of the R403Q-mutated MHC have been indefinite. For example, myosin isolated from myocardium of HCM patients carrying an allele for the R403Q mutation reportedly reduce (5) or enhance (33) actin filament velocity (V actin ) in the myosin motility assay. Additionally, actin-activated myosin ATPase and V actin of R403Q mutant MHC expressed by baculovirus/insect cell systems are reportedly reduced for rat cardiac ␣-MHC (44) and yet enhanced in chicken gizzard smooth muscle MHC (53).Data from mouse models of the R403Q mutation in ␣-MHC, on the other hand, have provided more consistent findings. Myosin isolated from myocardium of ␣-MHC R403Q/R403Q homozygous mice demonstrate a marked enhancement of actinactivated ATPase, V actin , and stall force of V actin by ␣-actinin (7, 47). Similarly, cardiac myosin isolated from ␣MHC R403Q/ϩ heterozygous mice shows enhanced ATPase (2, 31, 47). Data from ATPase and V actin assays generally correspond to each other and reflect actomyosin cross-bridge kinetics (48), whose enhancement in the R403Q myosin has been corroborated by a shorter cross-bridge time-on measured in the laser trap (47).Left ventricular (LV) function in the ␣MHC R403Q/ϩ heterozygous mouse, which mimics the human genotype leading to HCM, is characterized in part by an earlier and higher peak LV pressure and an elevated free wall fractional shorteni...

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Section: Discussionsupporting

confidence: 90%

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confidence: 64%

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confidence: 90%

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Myofilament mechanical performance is enhanced by R403Q myosin in mouse myocardium independent of sex

Palmer¹,

Wang²,

Teekakirikul³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…On the other hand, Ca 2+ sensitivity may remain the same although isometric force is reduced in soleus fibers of estrogen deficient ovariectomized rats 29 . Besides changes in the calcium mechanism, E2 can induce changes in the myosin filaments.…”

Section: Discussionmentioning

confidence: 94%

Muscle function in monozygotic female twin pairs discordant for hormone replacement therapy

et al. 2011

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Introduction: Postmenopausal monozygotic twin pairs discordant for hormone replacement therapy (HRT) provide an advantageous study design controlling for genetic background for elucidating the relationships between aging, sex hormone levels, muscle strength, contractile capacity, and fatigability. Methods: Thirteen postmenopausal monozygotic twin pairs discordant for HRT were measured for maximal voluntary torque (MVC) and twitch characteristics using electrical stimulation before and after intermittent dynamic plantarflexor exercise until exhaustion. Results: Peak twitch torque was 32% higher in HRT users than in their non‐HRT, genetically identical sisters (P = 0.002), but MVC did not differ. There were no differences in the activation level or twitch time characteristics between the co‐twins. Fatigue caused decreases in MVC (P = 0.001), twitch torque (P = 0.001), time to peak (P = 0.013), and half‐relaxation time (P = 0.001) similarly in HRT users and non–HRT users. Conclusion: In early postmenopausal women, involuntary but not voluntary force‐generating mechanisms of the plantarflexors are augmented by the use of HRT. Muscle Nerve, 2011

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“…In mouse models, contractile characteristics are impaired in muscles of ovariectomized compared with sham-operated mice (16,38,39,53,65). It was suggested (41) and subsequently demonstrated that ovarian hormones influence muscle strength by directly affecting the function of contractile proteins (43,66), particularly the structure and function of myosin (38,39). Among the ovarian hormones, 17␤-estradiol (E 2 ) appears to be the key hormone, because it reverses muscle weakness and contractile protein dysfunction caused by ovariectomy.…”

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confidence: 99%

Estradiol modulates myosin regulatory light chain phosphorylation and contractility in skeletal muscle of female mice

Lai

Collins

Colson

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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-Impairment of skeletal muscle function has been associated with changes in ovarian hormones, especially estradiol. To elucidate mechanisms of estradiol on skeletal muscle strength, the hormone's effects on phosphorylation of the myosin regulatory light chain (pRLC) and muscle contractility were investigated, hypothesizing an estradiol-specific beneficial impact. In a skeletal muscle cell line, C 2C12, pRLC was increased by 17␤-estradiol (E 2) in a concentration-dependent manner. In skeletal muscles of C57BL/6 mice that were E 2 deficient via ovariectomy (OVX), pRLC was lower than that from ovary-intact, sham-operated mice (Sham). The reduced pRLC in OVX muscle was reversed by in vivo E 2 treatment. Posttetanic potentiation (PTP) of muscle from OVX mice was low compared with that from Sham mice, and this decrement was reversed by acute E 2 treatment, demonstrating physiological consequence. Western blot of those muscles revealed that low PTP corresponded with low pRLC and higher PTP with greater pRLC. We aimed to elucidate signaling pathways affecting E 2-mediated pRLC using a kinase inhibitor library and C 2C12 cells as well as a specific myosin light chain kinase inhibitor in muscles. PI3K/Akt, MAPK, and CamKII were identified as candidate kinases sensitive to E 2 in terms of phosphorylating RLC. Applying siRNA strategy in C 2C12 cells, pRLC triggered by E 2 was found to be mediated by estrogen receptor-␤ and the G protein-coupled estrogen receptor. Together, these results provide evidence that E 2 modulates myosin pRLC in skeletal muscle and is one mechanism by which this hormone can affect muscle contractility in females. estrogen; estrogen receptor; kinase; post tetanic potentiation; RLC OVARIAN HORMONE DEFICIENCY is related to muscle dysfunction and loss of strength. For example, declines in strength are accelerated around the time of menopause (35,41,51), and skeletal muscles of postmenopausal women on estrogen-based hormone therapy are stronger than those not on hormone therapy (10,17,49). In mouse models, contractile characteristics are impaired in muscles of ovariectomized compared with sham-operated mice (16,38,39,53,65). It was suggested (41) and subsequently demonstrated that ovarian hormones influence muscle strength by directly affecting the function of contractile proteins (43,66), particularly the structure and function of myosin (38,39). Among the ovarian hormones, 17␤-estradiol (E 2 ) appears to be the key hormone, because it reverses muscle weakness and contractile protein dysfunction caused by ovariectomy. Specifically, reduced muscle and contractile protein functions were restored when E 2 was administered to ovariectomized mice (16,38,53). In a chemical model of premature aging, of which the ovaries of young adult mice were locally and specifically induced to be senescent, E 2 treatment improved some muscle contractile functions (18). Although these studies have demonstrated that E 2 impacts muscle and myosin functions, the molecular mechanisms by which this hormone affects the structure a...

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Differential effects of ovariectomy on calcium activation of cardiac and soleus myofilaments

Cited by 67 publications

References 28 publications

Myofilament mechanical performance is enhanced by R403Q myosin in mouse myocardium independent of sex

Myofilament mechanical performance is enhanced by R403Q myosin in mouse myocardium independent of sex

Muscle function in monozygotic female twin pairs discordant for hormone replacement therapy

Estradiol modulates myosin regulatory light chain phosphorylation and contractility in skeletal muscle of female mice

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