Divergent abnormal muscle relaxation by hypertrophic cardiomyopathy and nemaline myopathy mutant tropomyosins

2002 ◽  
Vol 9 (2) ◽  
pp. 103-111 ◽  
Author(s):  
Daniel E. Michele ◽  
Pierre Coutu ◽  
Joseph M. Metzger
Keyword(s):  
Skeletal Muscle ◽  
Hypertrophic Cardiomyopathy ◽  
Muscle Contraction ◽  
Cardiac Muscle ◽  
Muscle Weakness ◽  
Contractile Function ◽  
Muscle Relaxation ◽  
Nemaline Myopathy ◽  
Force Frequency ◽  
Cardiac Muscle Cells

Mutations in tropomyosin (Tm) have been linked to distinct inherited diseases of cardiac and skeletal muscle, hypertrophic cardiomyopathy (HCM), and nemaline myopathy (NM). How HCM and NM mutations in nearly identical Tm proteins produce the vastly divergent clinical phenotypes of heightened, prolonged cardiac muscle contraction in HCM and skeletal muscle weakness in NM is currently unknown. We report here a direct comparison of the effects of HCM (A63V) and NM (M9R) mutant Tm on membrane-intact myocyte contractile function as assessed by adenoviral gene transfer to fully differentiated cardiac muscle cells. Wild-type, and mutant HCM, and mutant NM proteins were expressed at similar levels in myocytes and incorporated into sarcomeres. Interestingly, HCM mutant Tm produced significantly longer contractions by slowing relaxation, whereas NM mutant Tm produced the opposite effect of accelerated muscle relaxation. We propose slowed relaxation caused by HCM mutant Tm can directly contribute to diastolic dysfunction seen in HCM even without secondary cardiac remodeling. Conversely, hastening of relaxation by NM mutant Tm may shift the force-frequency relationship in skeletal muscle and contribute to muscle weakness seen in NM. Together, these results implicate divergent, abnormal “turning off” of muscle contraction as a cellular basis for the differential pathogenesis of mutant Tm-associated HCM and NM.

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 CRISPR-Cas9 generated Pompe knock-in murine model exhibits early-onset hypertrophic cardiomyopathy and skeletal muscle weakness

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jeffrey Y. Huang ◽  
Shih-Hsin Kan ◽  
Emilie K. Sandfeld ◽  
Nancy D. Dalton ◽  
Anthony D. Rangel ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Hypertrophic Cardiomyopathy ◽  
Muscle Weakness ◽  
Murine Model ◽  
Early Onset ◽  
Skeletal Muscle Weakness

scholarly journals Short-Term Akt Activation in Cardiac Muscle Cells Improves Contractile Function in Failing Hearts

2012 ◽  
Vol 181 (6) ◽  
pp. 1969-1976 ◽  
Author(s):  
Ichiro Shiojima ◽  
Stephan Schiekofer ◽  
Jochen G. Schneider ◽  
Kurt Belisle ◽  
Kaori Sato ◽  
...  
Keyword(s):  
Cardiac Muscle ◽  
Contractile Function ◽  
Muscle Cells ◽  
Short Term ◽  
Cardiac Muscle Cells ◽  
Akt Activation

scholarly journals Enhanced Ca2+ transport and muscle relaxation in skeletal muscle from sarcolipin-null mice

2011 ◽  
Vol 301 (4) ◽  
pp. C841-C849 ◽  
Author(s):  
A. Russell Tupling ◽  
Eric Bombardier ◽  
Subash C. Gupta ◽  
Dawar Hussain ◽  
Chris Vigna ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Relaxation ◽  
Force Frequency ◽  
Relaxation Rates ◽  
Wild Type ◽  
Inhibitory Effects ◽  
Tetanic Force ◽  
Plasmic Reticulum ◽  
Force Relaxation ◽  
Frequency Curves

Sarcolipin (SLN) inhibits sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pumps. To evaluate the physiological significance of SLN in skeletal muscle, we compared muscle contractility and SERCA activity between Sln-null and wild-type mice. SLN protein expression in wild-type mice was abundant in soleus and red gastrocnemius (RG), low in extensor digitorum longus (EDL), and absent from white gastrocnemius (WG). SERCA activity rates were increased in soleus and RG, but not in EDL or WG, from Sln-null muscles, compared with wild type. No differences were seen between wild-type and Sln-null EDL muscles in force-frequency curves or maximum rates of force development (+dF/d t). Maximum relaxation rates (−dF/d t) of EDL were higher in Sln-null than wild type across a range of submaximal stimulation frequencies, but not during a twitch or peak tetanic contraction. For soleus, no differences were seen between wild type and Sln-null in peak tetanic force or +dF/d t; however, force-frequency curves showed that peak force during a twitch and 10-Hz contraction was lower in Sln-null. Changes in the soleus force-frequency curve corresponded with faster rates of force relaxation at nearly all stimulation frequencies in Sln-null compared with wild type. Repeated tetanic stimulation of soleus caused increased (−dF/d t) in wild type, but not in Sln-null. No compensatory responses were detected in analysis of other Ca2+ regulatory proteins using Western blotting and immunohistochemistry or myosin heavy chain expression using immunofluorescence. These results show that 1) SLN regulates Ca2+-ATPase activity thereby regulating contractile kinetics in at least some skeletal muscles, 2) the functional significance of SLN is graded to the endogenous SLN expression level, and 3) SLN inhibitory effects on SERCA function are relieved in response to repeated contractions thus enhancing relaxation rates.

scholarly journals Proto-oncogene expression in proliferating and differentiating cardiac and skeletal muscle

1987 ◽  
Vol 247 (3) ◽  
pp. 701-706 ◽  
Author(s):  
W C Claycomb ◽  
N A Lanson
Keyword(s):  
Skeletal Muscle ◽  
Cardiac Muscle ◽  
Muscle Tissue ◽  
Cellular Proliferation ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Specific Cell ◽  
Adult Rats ◽  
Cardiac Muscle Cells ◽  
Oncogene Expression

We have examined the expression of 13 proto-oncogenes in proliferating and terminally differentiated cardiac and skeletal muscle. Total RNA was prepared from intact ventricular cardiac-muscle tissue and from purified ventricular cardiac-muscle cells of neonatal and adult rats and from cultured proliferating and terminally differentiated L6A1 rat skeletal-muscle cells. cDNA probes for histone H4, thymidine kinase, myosin heavy chain and M-creatine kinase were used to assess cellular proliferation and differentiation. Oncogenes c-myc, c-raf, c-erb-A, c-ras-H, c-ski, and c-sis were expressed in both proliferating and differentiated cardiac muscle tissue and cells, whereas c-myb expression was not observed in either. c-src was expressed only in neonatal cardiac muscle tissue and cells. c-fms, c-abl, and c-ras-K were expressed in tissue from both neonatal and adult animals but only in purified cells from neonatal animals. c-fes/fps was expressed only in neonatal cardiac muscles cells. c-fos expression was not observed in cardiac-muscle tissue from either neonatal or adult rats, but surprisingly was abundantly expressed in freshly isolated cardiac-muscle cells from animals of both ages. These results emphasize that biochemical analysis using intact cardiac-muscle tissue may not necessarily reflect muscle-specific cell processes. They also show that the expression of c-fos can be activated by the cell isolation procedure. c-myc, c-ski, c-ras-H, c-ras-K, c-abl, c-raf and c-erb-A were expressed in both proliferating and terminally differentiated skeletal-muscle cells, whereas c-myb, c-fos, c-src and c-fms transcripts were observed only in proliferating cells. c-fes/fps and c-sis were not expressed in dividing or fused skeletal-muscle cells. These results demonstrate unique tissue and cell-specific patterns of proto-oncogene expression and suggest that these genes may be involved with the regulation of cellular proliferation and terminal differentiation in striated muscle.

Effects of N-acetylcysteine on in vitro diaphragm function are temperature dependent

1994 ◽  
Vol 77 (5) ◽  
pp. 2434-2439 ◽  
Author(s):  
P. T. Diaz ◽  
E. Brownstein ◽  
T. L. Clanton
Keyword(s):  
Skeletal Muscle ◽  
Salt Solution ◽  
Contractile Function ◽  
Recovery Period ◽  
Physiological Salt Solution ◽  
Force Frequency ◽  
Rat Diaphragm ◽  
Temperature Dependent ◽  
Diaphragm Function

Recent evidence has shown that systemic administration of N-acetylcysteine (NAC), a compound structurally similar to the intracellular antioxidant glutathione, inhibits skeletal muscle fatigue. To further elucidate the actions of NAC, we studied its effects on in vitro rat diaphragm contractile function. Rat diaphragm strips were incubated in tissue baths containing physiological salt solution (n = 29) or physiological salt solution containing 4 mg/ml of NAC (n = 29). Strips were stimulated by either indirect or direct means. After determination of baseline contractile characteristics, strips were fatigued for 4 min at 20 Hz (1 train/s, 0.33 ms train duration). Force-frequency relationships were then studied over a 60-min recovery period. We found that 1) NAC had significant effects on the baseline force-frequency relationship; treated strips had increased peak tension but diminished twitch tension and accelerated twitch kinetics; 2) NAC had significant fatigue-sparing effects that were magnified at 37 degrees C; and 3) NAC treatment did not improve postfatigue recovery. The effects of NAC were generally independent of the stimulation method. We conclude that NAC has direct temperature-dependent effects on diaphragm function. These effects are consistent with the properties of NAC as an antioxidant and suggest important but complex effects of oxidant stress on skeletal muscle.

scholarly journals Skeletal myofiber VEGF regulates contraction-induced perfusion and exercise capacity but not muscle capillarity in adult mice

2016 ◽  
Vol 311 (1) ◽  
pp. R192-R199 ◽  
Author(s):  
Amy E. Knapp ◽  
Daniel Goldberg ◽  
Hamid Delavar ◽  
Breanna M. Trisko ◽  
Kechun Tang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Contraction ◽  
Exercise Capacity ◽  
Fatigue Resistance ◽  
Gene Deletion ◽  
Endurance Capacity ◽  
Force Frequency ◽  
Vegf Gene ◽  
Adult Mice ◽  
Skeletal Myofiber

A single bout of exhaustive exercise signals expression of vascular endothelial growth factor (VEGF) in the exercising muscle. Previous studies have reported that mice with life-long deletion of skeletal myofiber VEGF have fewer capillaries and a severe reduction in endurance exercise. However, in adult mice, VEGF gene deletion conditionally targeted to skeletal myofibers limits exercise capacity without evidence of capillary regression. To explain this, we hypothesized that adult skeletal myofiber VEGF acutely regulates skeletal muscle perfusion during muscle contraction. A tamoxifen-inducible skeletal myofiber-specific VEGF gene deletion mouse (skmVEGF−/−) was used to reduce skeletal muscle VEGF protein by 90% in adult mice. Three weeks after inducing deletion of the skeletal myofiber VEGF gene, skmVEGF−/− mice exhibited diminished maximum running speed (−10%, P < 0.05) and endurance capacity (−47%; P < 0.05), which did not persist after 8 wk. In skmVEGF−/− mice, gastrocnemius complex time to fatigue measured in situ was 71% lower than control mice. Contraction-induced perfusion measured by optical imaging during a period of electrically stimulated muscle contraction was 85% lower in skmVEGF−/− than control mice. No evidence of capillary rarefication was detected in the soleus, gastrocnemius, and extensor digitorum longus (EDL) up to 8 wk after tamoxifen-induced VEGF ablation, and contractility and fatigue resistance of the soleus measured ex vivo were also unchanged. The force-frequency of the EDL showed a small right shift, but fatigue resistance did not differ between EDL from control and skmVEGF−/− mice. These data suggest myofiber VEGF is required for regulating perfusion during periods of contraction and may in this manner affect endurance capacity.

Aging augments interstitial K+ concentrations in active muscle of rats

2006 ◽  
Vol 100 (4) ◽  
pp. 1158-1163 ◽  
Author(s):  
Jianhua Li ◽  
Lawrence I. Sinoway ◽  
Yuk-Chow Ng
Keyword(s):  
Skeletal Muscle ◽  
Muscle Contraction ◽  
Contractile Function ◽  
Large Body ◽  
Specific Inhibitor ◽  
Muscle Performance ◽  
Brown Norway ◽  
Aged Rats ◽  
Adult Rats ◽  
Adult Skeletal Muscle

Skeletal muscle performance declines with advancing age, and the underlying mechanism is not completely understood. A large body of convincing evidence has demonstrated a crucial role for interstitial K+ concentration ([K+]o) in modulating contractile function of skeletal muscle. The present study tested the hypothesis that during muscle contraction there is a greater accumulation of [K+]o in aged compared with adult skeletal muscle. Twitch muscle contraction was induced by electrical stimulation of the sciatic nerves of 8- and 32-mo-old Fischer 344 × Brown Norway rats. Levels of [K+]o were measured continuously by a microdialysis technique with the probes inserted into the gastrocnemius muscle. Stimulation at 1, 3, and 5 Hz elevated muscle [K+]o by 52, 64, and 88% in adult rats, and by 78, 98, and 104% in aged rats, respectively, and the increase was significantly higher in aged than in adult rats. Recovery for [K+]o, as measured by the time for [K+]o to recover by 20 and 50% from peak response after stimulation, was slower in aged rats. Ouabain (5 mM), a specific inhibitor of the Na+-K+ pump, was added in the perfusate to inhibit the reuptake of K+ into the cells to assess the role of the pump in the overall K+ balance. Ouabain elevated muscle [K+]o at rest, and the effect was significantly attenuated in aged animals. The present data demonstrated an augmented [K+]o in aged skeletal muscle compared with adult skeletal muscle, and the data suggested that an alteration in the function of the Na+-K+ pump may contribute, in part, to the deficiency in K+ balance in skeletal muscle of aged rats.

Metabolic responses from rest to steady state determine contractile function in ischemic skeletal muscle

1997 ◽  
Vol 273 (2) ◽  
pp. E233-E238 ◽  
Author(s):  
J. A. Timmons ◽  
S. M. Poucher ◽  
D. Constantin-Teodosiu ◽  
I. A. Macdonald ◽  
P. L. Greenhaff
Keyword(s):  
Skeletal Muscle ◽  
Steady State ◽  
Muscle Contraction ◽  
Metabolic Response ◽  
Contractile Function ◽  
Pyruvate Dehydrogenase Complex ◽  
Force Production ◽  
Critical Factor ◽  
Control Group ◽  
State Force

Skeletal muscle contraction during ischemia, such as that experienced by peripheral vascular disease patients, is characterized by rapid fatigue. Using a canine gracilis model, we tested the hypothesis that a critical factor determining force production during ischemia is the metabolic response during the transition from rest to steady state. Dichloroacetate (DCA) administration before gracilis muscle contraction increased pyruvate dehydrogenase complex activation and resulted in acetylation of 80% of the free carnitine pool to acetylcarnitine. After 1 min of contraction, phosphocreatine (PCr) degradation in the DCA group was approximately 50% lower than in the control group (P < 0.05) during conditions of identical force production. After 6 min of contraction, steady-state force production was approximately 30% higher in the DCA group (P < 0.05), and muscle ATP, PCr, and glycogen degradation and lactate accumulation were lower (P < 0.05 in all cases). It appears, therefore, that an important determinant of contractile function during ischemia is the mechanisms by which ATP regeneration occurs during the period of rest to steady-state transition.

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