scholarly journals Impact of estrogen deficiency on diaphragm and leg muscle contractile function in female mdx mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0249472
Author(s):  
Pangdra Vang ◽  
Cory W. Baumann ◽  
Rebecca Barok ◽  
Alexie A. Larson ◽  
Brendan J. Dougherty ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Strength ◽  
Contractile Function ◽  
Estrogen Deficiency ◽  
Diaphragm Muscle ◽  
Whole Body ◽  
Ventilatory Function ◽  
Fourth Decade ◽  
Muscle Contractile

Female carriers of Duchenne muscular dystrophy (DMD) presenting with DMD symptomology similar to males with DMD, such as skeletal muscle weakness and cardiomyopathy, are termed manifesting carriers. There is phenotypic variability among manifesting carriers including the age of onset, which can range from the first to fourth decade of life. In females, estrogen levels typically begin to decline during the fourth decade of life and estrogen deficiency contributes to loss of muscle strength and recovery of strength following injury. Thus, we questioned whether the decline of estrogen impacts the development of DMD symptoms in females. To address this question, we studied 6–8 month-old homozygous mdx female mice randomly assigned to a sham or ovariectomy (OVX) surgical group. In vivo whole-body plethysmography assessed ventilatory function and diaphragm muscle strength was measured in vitro before and after fatigue. Anterior crural muscles were analyzed in vivo for contractile function, fatigue, and in response to eccentric contraction (ECC)-induced injury. For the latter, 50 maximal ECCs were performed by the anterior crural muscles to induce injury. Body mass, uterine mass, hypoxia-hypercapnia ventilatory response, and fatigue index were analyzed by a pooled unpaired t-test. A two-way ANOVA was used to analyze ventilatory measurements. Fatigue and ECC-injury recovery experiments were analyzed by a two-way repeated-measures ANOVA. Results show no differences between sham and OVX mdx mice in ventilatory function, strength, or recovery of strength after fatigue in the diaphragm muscle or anterior crural muscles (p ≥ 0.078). However, OVX mice had significantly greater eccentric torque loss and blunted recovery of strength after ECC-induced injury compared to sham mice (p ≤ 0.019). Although the results show that loss of estrogen has minimal impact on skeletal muscle contractile function in female mdx mice, a key finding suggests that estrogen is important in muscle recovery in female mdx mice after injury.

scholarly journals Global phosphoproteomic profiling of skeletal muscle in ovarian hormone-deficient female mice

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 675-676
Author(s):  
Mina Peyton ◽  
Tzu-Yi Yang ◽  
LeeAnn Higgins ◽  
Todd Markowski ◽  
Laurie Parker ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Strength ◽  
Contractile Function ◽  
Fiber Type ◽  
Tibialis Anterior Muscle ◽  
Estrogen Deficiency ◽  
Post Translational Modification ◽  
Coupling Energy ◽  
Age Related ◽  
Skeletal Muscle Strength

Abstract Dynapenia, the age-related loss of skeletal muscle strength without the loss of muscle mass, significantly impacts the activities and quality of life of the aging population. Studies have shown that dynapenia occurs earlier in females than males in both human and rodent studies. Moreover, in females, estrogen deficiency has been shown to contribute to the loss of skeletal muscle strength as well as blunted recovery of strength after injury. The maintenance of skeletal muscle contractile function is vital to the overall health of women, especially as women live 1/3 of their life in an estrogen deficient state. Reversible protein phosphorylation is an indispensable post-translational modification, playing a key role in signal transduction pathways. Phosphorylation of skeletal muscle proteins have been shown to regulate sarcomeric function, excitation-contraction coupling, energy metabolism, and fiber-type composition. To define the physiological changes in the skeletal muscle phosphoproteome associated with estrogen deficiency, we used an ovariectomy model coupled with mass spectrometry. We identified, in total, 5,424 unique phosphorylation sites and 1,177 phosphoproteins in the tibialis anterior muscle. Ingenuity Pathway Analysis show decreased phosphorylation of contractile proteins and significant predicted inhibition of the upstream kinase, CDK6 (z-score -2.0) in ovariectomized compared to control muscles. Our results suggest that estrogen deficiency remodels the skeletal muscle phosphoproteome which may alter phosphorylation signaling that might contribute to the loss of strength in females.

scholarly journals Combined overexpression of SIRT1 and knockout of GCN5 in adult skeletal muscle does not affect glucose homeostasis or exercise performance in mice

2020 ◽  
Vol 318 (2) ◽  
pp. E145-E151 ◽  
Author(s):  
Kristoffer Svensson ◽  
Shahriar Tahvilian ◽  
Vitor F. Martins ◽  
Jessica R. Dent ◽  
Adrianna Lemanek ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Homeostasis ◽  
Mitochondrial Biogenesis ◽  
Exercise Performance ◽  
Wheel Running ◽  
Contractile Function ◽  
Muscle Contractile ◽  
Combined Overexpression ◽  
Voluntary Wheel

Sirtuin 1 (SIRT1) and general control of amino acid synthesis 5 (GCN5) regulate mitochondrial biogenesis via opposing modulation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) acetylation status and activity. However, the combined contribution of SIRT1 and GCN5 to skeletal muscle metabolism and endurance performance in vivo is unknown. In this study, we investigated the impact of combined skeletal muscle-specific overexpression of SIRT1 and deletion of GCN5 on glucose homeostasis, skeletal muscle mitochondrial biogenesis and function, and metabolic adaptation to endurance exercise training in mice. We generated mice with combined and tamoxifen-inducible skeletal muscle-specific overexpression of SIRT1 and knockout of GCN5 (dTG) and floxed [wild type (WT)] littermates using a Cre-LoxP approach. All mice were treated with tamoxifen at 5–6 wk of age, and 4–7 wk later glucose homeostasis, skeletal muscle contractile function, mitochondrial function, and the effects of 14 days of voluntary wheel running on expression of metabolic proteins and exercise capacity were assessed. There was no difference in oral glucose tolerance, skeletal muscle contractile function, mitochondrial abundance, or maximal respiratory capacity between dTG and WT mice. Additionally, there were no genotype differences in exercise performance and markers of mitochondrial biogenesis after 14 days of voluntary wheel running. These results demonstrate that combined overexpression of SIRT1 and loss of GCN5 in vivo does not promote metabolic remodeling in skeletal muscle of sedentary or exercise-trained mice.

scholarly journals Deletion of estrogen receptor α in skeletal muscle results in impaired contractility in female mice

2018 ◽  
Vol 124 (4) ◽  
pp. 980-992 ◽  
Author(s):  
Brittany C. Collins ◽  
Tara L. Mader ◽  
Christine A. Cabelka ◽  
Melissa R. Iñigo ◽  
Espen E. Spangenburg ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Estrogen Receptor ◽  
Muscle Strength ◽  
Body Mass ◽  
Light Chain ◽  
Knockout Mice ◽  
Contractile Function ◽  
Estrogen Receptor Α ◽  
Myosin Regulatory Light Chain

Estradiol deficiency in females can result in skeletal muscle strength loss, and treatment with estradiol mitigates the loss. There are three primary estrogen receptors (ERs), and estradiol elicits effects through these receptors in various tissues. Ubiquitous ERα-knockout mice exhibit numerous biological disorders, but little is known regarding the specific role of ERα in skeletal muscle contractile function. The purpose of this study was to determine the impact of skeletal muscle-specific ERα deletion on contractile function, hypothesizing that ERα is a main receptor through which estradiol affects muscle strength in females. Deletion of ERα specifically in skeletal muscle (skmERαKO) did not affect body mass compared with wild-type littermates (skmERαWT) until 26 wk of age, at which time body mass of skmERαKO mice began to increase disproportionally. Overall, skmERαKO mice had low strength demonstrated in multiple muscles and by several contractile parameters. Isolated extensor digitorum longus muscles from skmERαKO mice produced 16% less eccentric and 16–26% less submaximal and maximal isometric force, and isolated soleus muscles were more fatigable, with impaired force recovery relative to skmERαWT mice. In vivo maximal torque productions by plantarflexors and dorsiflexors were 16% and 12% lower in skmERαKO than skmERαWT mice, and skmERαKO muscles had low phosphorylation of myosin regulatory light chain. Plantarflexors also generated 21–32% less power, submaximal isometric and peak concentric torques. Data support the hypothesis that ablation of ERα in skeletal muscle results in muscle weakness, suggesting that the beneficial effects of estradiol on muscle strength are receptor mediated through ERα. NEW & NOTEWORTHY We comprehensively measured in vitro and in vivo skeletal muscle contractility in female estrogen receptor α (ERα) skeletal muscle-specific knockout mice and report that force generation is impaired across multiple parameters. These results support the hypothesis that a primary mechanism through which estradiol elicits its effects on strength is mediated by ERα. Evidence is presented that estradiol signaling through ERα appears to modulate force at the molecular level via posttranslational modifications of myosin regulatory light chain.

scholarly journals Skeletal muscle dysfunction is associated with derangements in mitochondrial bioenergetics (but not UCP3) in a rodent model of sepsis

2015 ◽  
Vol 308 (9) ◽  
pp. E713-E725 ◽  
Author(s):  
Parjam S. Zolfaghari ◽  
Jane E. Carré ◽  
Nadeene Parker ◽  
Nancy A. Curtin ◽  
Michael R. Duchen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Membrane Potential ◽  
Contractile Function ◽  
Uncoupling Protein ◽  
Coupling Efficiency ◽  
Diaphragm Muscle ◽  
Whole Body ◽  
Proton Leak ◽  
Muscle Dysfunction ◽  
Wild Type

Muscle dysfunction is a common feature of severe sepsis and multiorgan failure. Recent evidence implicates bioenergetic dysfunction and oxidative damage as important underlying pathophysiological mechanisms. Increased abundance of uncoupling protein-3 (UCP3) in sepsis suggests increased mitochondrial proton leak, which may reduce mitochondrial coupling efficiency but limit reactive oxygen species (ROS) production. Using a murine model, we examined metabolic, cardiovascular, and skeletal muscle contractile changes following induction of peritoneal sepsis in wild-type and Ucp3−/−mice. Mitochondrial membrane potential (Δψm) was measured using two-photon microscopy in living diaphragm, and contractile function was measured in diaphragm muscle strips. The kinetic relationship between membrane potential and oxygen consumption was determined using a modular kinetic approach in isolated mitochondria. Sepsis was associated with significant whole body metabolic suppression, hypothermia, and cardiovascular dysfunction. Maximal force generation was reduced and fatigue accelerated in ex vivo diaphragm muscle strips from septic mice. Δψmwas lower in the isolated diaphragm from septic mice despite normal substrate oxidation kinetics and proton leak in skeletal muscle mitochondria. Even though wild-type mice exhibited an absolute 26 ± 6% higher UCP3 protein abundance at 24 h, no differences were seen in whole animal or diaphragm physiology, nor in survival rates, between wild-type and Ucp3−/−mice. In conclusion, this murine sepsis model shows a hypometabolic phenotype with evidence of significant cardiovascular and muscle dysfunction. This was associated with lower Δψmand alterations in mitochondrial ATP turnover and the phosphorylation pathway. However, UCP3 does not play an important functional role, despite its upregulation.

Differential effects of anesthetics on in vivo skeletal muscle contractile function in the mouse

1996 ◽  
Vol 80 (1) ◽  
pp. 332-340 ◽  
Author(s):  
C. P. Ingalls ◽  
G. L. Warren ◽  
D. A. Lowe ◽  
D. B. Boorstein ◽  
R. B. Armstrong
Keyword(s):  
Skeletal Muscle ◽  
Contractile Function ◽  
Average Power ◽  
Eccentric Contraction ◽  
Peak Torque ◽  
High Dose ◽  
Skeletal Muscle Function ◽  
Contractile Responses ◽  
Time Integral

The purpose of this study was to evaluate the effects of four anesthetic regimens on in vivo contractile function of mouse ankle dorsiflexor muscles. The torque-frequency and torque-velocity relationships were determined for the following anesthetics: fentanyl-droperidol and diazepam (F-d/d); ketamine and xylazine (K/x); pentobarbital sodium (Ps); and methoxyflurane (Mf). Mf, Ps, and F-d/d regimens resulted in comparable contractile responses at low doses, whereas K/x produced a relative depression in isometric contractile function as shown by a decrease in the torque-time integral at the 300-Hz stimulation frequency (-13.9%; P < 0.05). Moreover, K/x caused a shift to the left in the torque-frequency curve as indicated by increases in torque-time integrals at 25 and 50 Hz. Both Ps and F-d/d regimens exhibited dose-dependent effects during the isovelocity contractions. Ps significantly reduced work (-28.7%) and average power (-28.9%) at 800 degrees/s at the high dose. In contrast, F-d/d anesthesia resulted in increases in peak torque (16-20%) and work (15-18%) output at all eccentric contraction velocities at the high dose, whereas average power was increased only at -800 (17%) and -1,000 degrees/s (17%). In conclusion, commonly used anesthetic regimens can affect the contractile response in vivo; K/x and Ps yield smaller torque outputs, whereas Mf and F-d/d consistently produce larger contractile responses. Mf and F-d/d are recommended for use in studying skeletal muscle function in mice in vivo.

scholarly journals Dysfunction of muscle contraction with impaired intracellular Ca2+ handling in skeletal muscle and the effect of exercise training in male db/db mice

2019 ◽  
Vol 126 (1) ◽  
pp. 170-182 ◽  
Author(s):  
Hiroaki Eshima ◽  
Yoshifumi Tamura ◽  
Saori Kakehi ◽  
Kyoko Nakamura ◽  
Nagomi Kurebayashi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Exercise Training ◽  
Muscle Contraction ◽  
Contractile Function ◽  
Contractile Force ◽  
Contractile Dysfunction ◽  
Muscle Contractile ◽  
Type 2 Diabetic

Type 2 diabetes is characterized by reduced contractile force production and increased fatigability of skeletal muscle. While the maintenance of Ca2+ homeostasis during muscle contraction is a requisite for optimal contractile function, the mechanisms underlying muscle contractile dysfunction in type 2 diabetes are unclear. Here, we investigated skeletal muscle contractile force and Ca2+ flux during contraction and pharmacological stimulation in type 2 diabetic model mice ( db/db mice). Furthermore, we investigated the effect of treadmill exercise training on muscle contractile function. In male db/db mice, muscle contractile force and peak Ca2+ levels were both lower during tetanic stimulation of the fast-twitch muscles, while Ca2+ accumulation was higher after stimulation compared with control mice. While 6 wk of exercise training did not improve glucose tolerance, exercise did improve muscle contractile dysfunction, peak Ca2+ levels, and Ca2+ accumulation following stimulation in male db/db mice. These data suggest that dysfunctional Ca2+ flux may contribute to skeletal muscle contractile dysfunction in type 2 diabetes and that exercise training may be a promising therapeutic approach for dysfunctional skeletal muscle contraction. NEW & NOTEWORTHY The purpose of this study was to examine muscle contractile function and Ca2+ regulation as well as the effect of exercise training in skeletal muscle in obese diabetic mice ( db/db). We observed impairment of muscle contractile force and Ca2+ regulation in a male type 2 diabetic animal model. These dysfunctions in muscle were improved by 6 wk of exercise training.

scholarly journals Effects of fasting on isolated murine skeletal muscle contractile function during acute hypoxia

PLoS ONE ◽  
2020 ◽  
Vol 15 (4) ◽  
pp. e0225922
Author(s):  
Cameron A. Schmidt ◽  
Emma J. Goldberg ◽  
Tom D. Green ◽  
Reema R. Karnekar ◽  
Jeffrey J. Brault ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Contractile Function ◽  
Acute Hypoxia ◽  
Murine Skeletal Muscle ◽  
Muscle Contractile

scholarly journals Fatigue alters in vivo function within and between limb muscles during locomotion

2008 ◽  
Vol 276 (1659) ◽  
pp. 1193-1197 ◽  
Author(s):  
Timothy E Higham ◽  
Andrew A Biewener
Keyword(s):  
Muscle Function ◽  
Contractile Function ◽  
Force Generation ◽  
Whole Body ◽  
Activation Patterns ◽  
Reduction In Force ◽  
Numida Meleagris ◽  
Limb Kinematics ◽  
Specific Alteration

Muscle fatigue, a reduction in force as a consequence of exercise, is an important factor for any animal that moves, and can result from both peripheral and/or central mechanisms. Although much is known about whole-limb force generation and activation patterns in fatigued muscles under sustained isometric contractions, little is known about the in vivo dynamics of limb muscle function in relation to whole-body fatigue. Here we show that limb kinematics and contractile function in the lateral (LG) and medial (MG) gastrocnemius of helmeted guineafowl ( Numida meleagris ) are significantly altered following fatiguing exercise at 2 m s −1 on an inclined treadmill. The two most significant findings were that the variation in muscle force generation, measured directly from the muscles' tendons, increased significantly with fatigue, and fascicle shortening in the proximal MG, but not the distal MG, decreased significantly with fatigue. We suggest that the former is a potential mechanism for decreased stability associated with fatigue. The region-specific alteration of fascicle behaviour within the MG as a result of fatigue suggests a complex response to fatigue that probably depends on muscle–aponeurosis and tendon architecture not previously explored. These findings highlight the importance of studying the integrative in vivo dynamics of muscle function in response to fatigue.

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