New insights on contraction efficiency in patients with Duchenne muscular dystrophy

The decrease in muscle strength in patients with Duchenne muscular dystrophy (DMD) is mainly explained by a decrease in the number of active contractile elements. Nevertheless, it is possible that other electrochemical and force transmission processes may contribute. The present study aimed to quantify the effect of DMD on the relative contribution of electrochemical and force transmission components of the electromechanical delay (i.e., time lag between the onset of muscle activation and force production) in humans using very high frame rate ultrasound. Fourteen patients with DMD and thirteen control subjects underwent two electrically evoked contractions of the biceps brachii with the ultrasound probe over the muscle belly. The electromechanical delay was significantly longer in DMD patients compared with controls (18.5 ± 3.9 vs. 12.5 ± 1.4 ms, P < 0.0001). More precisely, DMD patients exhibited a longer delay between the onset of muscle fascicles motion and force production (13.6 ± 3.1 vs. 7.9 ± 2.0 ms, P < 0.0001). This delay was correlated to the chronological age of the DMD patients ( r = 0.66; P = 0.01), but not of the controls ( r = −0.45; P = 0.10). No significant difference was found for the delay between the onset of muscle stimulation and the onset of muscle fascicle motion. These results highlight the role of the alteration of muscle force transmission (delay between the onset of fascicle motion and force production) in the impairments of the contraction efficiency in patients with DMD.

Download Full-text

Hyperthermia reduces electromechanical delay via accelerated electrochemical processes

Journal of Applied Physiology ◽

10.1152/japplphysiol.00538.2020 ◽

2020 ◽

Author(s):

Adèle Mornas ◽

Sebastien Racinais ◽

Franck Brocherie ◽

Marine Alhammoud ◽

Robin Hager ◽

...

Keyword(s):

Relative Humidity ◽

Heat Exposure ◽

Force Production ◽

Frame Rate ◽

Force Transmission ◽

Electromechanical Delay ◽

Ambient Environment ◽

Electrochemical Processes ◽

Muscle Fascicle ◽

Voluntary Contractions

The present study aimed to determine the effect of hyperthermia on both electrochemical and mechanical components of the electromechanical delay (EMD), using very-high-frame-rate ultrasound. Electrically evoked peak twitch force, EMD, electrochemical (Dm, i.e., delay between stimulation and muscle fascicle motion) and mechanical (Tm, i.e., delay between fascicle motion and force production onset) components of EMD were assessed in sixteen participants. Assessments were conducted in a control ambient environment (CON: 26°C, 34% relative humidity) and in hot ambient environment (HOT: 46-50°C, 18% relative humidity, after ~127 min of heat exposure). Following heat exposure, gastrocnemius medialis temperature was 37.0 ± 0.6°C in HOT vs. 34.0 ± 0.8°C in CON (P < 0.001). EMD was shorter (9.4 ± 0.8 ms) in HOT than CON (10.8 ± 0.6 ms, P < 0.001). Electrochemical processes were shorter in HOT than CON (4.0 ± 0.8 ms vs. 5.5 ± 0.9 ms, respectively, P < 0.001), while mechanical processes were unchanged (P = 0.622). These results demonstrate that hyperthermia reduces electromechanical delay via accelerated electrochemical processes while force transmission along the active and passive parts of the series elastic component is not affected following heat exposure. The present study demonstrates that heat exposure accelerates muscle contraction thanks to faster electrochemical processes. Further investigations during voluntary contractions would contribute to better understand how these findings translate into motor performance.

Download Full-text

Abstract 522: Impaired Inside-out Force Transmission in Hipsc-cardiomyocyte Model of Duchenne Muscular Dystrophy Cardiomyopathy

Circulation Research ◽

10.1161/res.127.suppl_1.522 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Gaspard Pardon ◽

Foster Birnbaum ◽

Asuka Eguchi ◽

Helen M BLAU

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Disease Progression ◽

Microcontact Printing ◽

Early Adulthood ◽

Force Production ◽

Traction Force ◽

Cardiac Contraction ◽

Cellular Stress Response ◽

Force Transmission

Duchenne Muscular Dystrophy (DMD) is a lethal X-chromosome linked disease that affects ~1:3500 boys and culminates in heart failure in early adulthood. DMD results from >200 possible dystrophin mutations. The lack of dystrophin disrupts the anchoring of the sarcomere to the extracellular matrix (ECM), impairing cardiomyocyte function and cardiac contraction. With disease progression, the heart tissue stiffness increases as fibrosis progresses and a dilated cardiomyopathy phenotype develops. We hypothesize that disease progression accelerates because of a positive feedback loop involving fibrotic stiffening and mechanosensing. Our preliminary results show that single human-derived pluripotent stem cell (hiPSC) cardiomyocytes (CMs) with DMD mutations have a dramatically reduced ability to produce force compared to isogenic controls on stiffer substrates mimicking a fibrotic state, but not on soft healthy substrates. This stiffness-dependent contractile deficiency correlates with an increase in reactive oxygen species (ROS) and mitochondrial dysfunction, as well as other markers of cellular stress response and senescence. Here, we ask how stiffness affects the progression of DMD cardiomyopathy and aim to draw a link between the lack of dystrophin and force production deficiency in hiPSC-CMs with or without DMD mutations in an isogenic background. Using a novel assay and algorithm, we simultaneously measure extracellular force production by traction force microscopy (TFM) and single sarcomere dynamics (SSD) in single hiPSC-CMs adhered onto ECM micropatterns on top of a hydrogel of stiffness matching that of healthy (~10kPa) or fibrotic (~35kPa) tissue. We induce the single hiPSC-CMs to adopt a physiologic elongated 1:7 aspect ratio using microcontact printing of ECM protein. Using this platform, we determine how the lack of dystrophin impacts sarcomere architecture, sarcomere contractility, and force generation in the etiology of DMD cardiac disease.

Download Full-text

Abstract 697: Dyssynchrony in Duchenne Muscular Dystrophy Demonstrated by Tagged MRI Analysis is Independent of Ejection Fraction

Circulation ◽

10.1161/circ.118.suppl_18.s_601 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

William M Gottliebson ◽

Wojciech Mazur ◽

Janaka Wansapura ◽

D. W Benson ◽

Kan N Hor

Keyword(s):

Heart Rate ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Ejection Fraction ◽

Cardiac Mri ◽

Circumferential Strain ◽

Coronary Perfusion ◽

Peak Strain ◽

Tagged Mri ◽

Significant Difference

Patients with Duchenne Muscular Dystrophy (DMD), a dystrophinopathy, universally develop dilated cardiomyopathy, which is associated with abnormal myocardial strain, as well as heterogeneous development of fibrosis as demonstrated by pathology and more recently by cardiac MRI methods. We sought to determine the presence of systolic dyssynchrony in this population using cardiac MRI tagging methods. We analyzed tagged MRI images for the presence of dyssynchrony in 61 males (age 12.5 ± 4.4 y) with a dystrophin mutation undergoing clinical cardiac MRI. Tagged MRI images were analyzed using HARP® analysis of regional strain and strain-time curves. The mid-myocardial slice was specifically analyzed, by dividing it into 6 coronary perfusion regions. Dyssynchrony was defined by the presence of either of 2 previously published indexes modified for use with MRI data: 1) time difference of 1 st to last regional peak strain > 100 ms; 2) standard deviation of time differences to peak strain for each of the six regions > 33 ms. Additional indexes evaluated included heart rate, LV ejection fraction, mid-myocardial composite circumferential strain, and presence of delayed myocardial hyperenhancement (MDE). Among the 61 subjects analyzed, 28 (46%) exhibited dyssynchrony indexes 1 and 2, while 8 additional subjects met dyssynchrony index 2 but not index 1. Only 4 subjects, all of whom met both dyssynchrony criteria, had positive MDE and abnormal EF <55%. The regions of slowest activation were highly dispersed and not clustered to the areas of positive MDE. One additional subject with dyssynchrony by either of the critieria also had abnormal EF but did not have MDE. There was no statistically significant difference between mean EF (61 vs 62%), age (12.58 vs 12.63 yrs), heart rate (105 vs 108 bpm) or mid-myocardial composite circumferential strain (−13.3 vs −12.9%) between those subjects with dyssynchrony (by either criteria) and those without. DMD patients frequently exhibit systolic dyssynchrony even in the presence of normal EF. However, the dispersed nature of the dyssynchrony suggests that resynchronization therapy once EF becomes abnormal is unlikely to be of benefit in DMD cardiomyopathy.

Download Full-text

Dystrophin Deficiency Compromises Force Production of the Extensor Carpi Ulnaris Muscle in the Canine Model of Duchenne Muscular Dystrophy

PLoS ONE ◽

10.1371/journal.pone.0044438 ◽

2012 ◽

Vol 7 (9) ◽

pp. e44438 ◽

Cited By ~ 16

Author(s):

Hsiao T. Yang ◽

Jin-Hong Shin ◽

Chady H. Hakim ◽

Xiufang Pan ◽

Ronald L. Terjung ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Force Production ◽

Canine Model ◽

Extensor Carpi Ulnaris ◽

Dystrophin Deficiency

Download Full-text

The Evaluation of Muscle Activation in Climbing up Stairs Activity in Children With Duchenne Muscular Dystrophy

Case Medical Research ◽

10.31525/ct1-nct04287582 ◽

2020 ◽

Author(s):

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Muscle Activation

Download Full-text

Activation of Antagonist Knee Muscles during Isokinetic Efforts in Prepubertal and Adult Males

Pediatric Exercise Science ◽

10.1123/pes.17.2.171 ◽

2005 ◽

Vol 17 (2) ◽

pp. 171-181 ◽

Cited By ~ 7

Author(s):

Eleni Bassa ◽

Dimitrios Patikas ◽

Christos Kotzamanidis

Keyword(s):

Muscle Activation ◽

Vastus Lateralis ◽

Force Production ◽

Biceps Femoris ◽

Antagonistic Activity ◽

Adult Males ◽

Significant Difference ◽

Angular Velocities ◽

Knee Muscle ◽

Muscle Force Production

The deficit of muscle-force production observed in children can be partly attributed to neural factors, such as an increased level of coactivation. This hypothesis, however, has not been thoroughly investigated under concentric and eccentric isokinetic conditions at different angular velocities. Thus, the purpose of this study was to examine whether prepubescent children present higher levels of activation of the antagonist knee muscles during isokinetic, concentric, and eccentric knee efforts compared with adults. Eighteen prepubertal and 13 young adult males (age: 10.9 ± 0.5 and 18.1 ± 0.1 years, respectively) performed maximal concentric and eccentric knee extensions and flexions at 45, 90, and 180 degrees/s. The vastus lateralis and biceps femoris electromyogram was recorded and the antagonist activation (coactivation) was calculated. Concentric contractions for both groups revealed significantly higher coactivation values (p < .05) compared with the eccentric conditions. Furthermore, increasing the angular velocity increased the level of coactivation significantly only during the concentric efforts for both groups. No significant difference in the antagonistic activity of the vastus lateralis and biceps femoris, however, was found between groups. Therefore, increased antagonist knee-muscle activation, which enhances joint stabilization during isokinetic concentric and eccentric effort, is similar in both prepubescent and adult males.

Download Full-text

Effects of HOCl oxidation on excitation–contraction coupling: Implications for the pathophysiology of Duchenne muscular dystrophy

The Journal of General Physiology ◽

10.1085/jgp.2021ecc16 ◽

2021 ◽

Vol 154 (9) ◽

Author(s):

Thomas A. Lea ◽

Gavin J. Pinniger ◽

Peter G. Arthur ◽

Tony J. Bakker

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Chronic Inflammation ◽

Hypochlorous Acid ◽

Force Production ◽

Mdx Mice ◽

Potential Contribution ◽

Myeloperoxidase Activity ◽

Excitation Contraction Coupling ◽

Contraction Coupling

Duchenne muscular dystrophy (DMD) is a fatal X-linked genetic disease characterized by progressive loss of skeletal muscle. The mechanisms underlying the DMD pathology likely involve the complex interaction between reactive oxygen species (ROS) impaired Ca2+ handling and chronic inflammation, characterized by the presence of immune cells such as neutrophils. Hypochlorous acid (HOCl) is a highly reactive form of ROS produced endogenously via the actions of myeloperoxidase, an enzyme secreted by neutrophils. Myeloperoxidase activity is significantly elevated in dystrophic muscle. This study aimed to determine the effect of HOCl exposure on excitation–contraction coupling and its potential contribution to the dystrophic pathology. Isolated extensor digitorum longus (EDL) muscles and single fibers from C57 (wild type) and mdx (dystrophic) mice were used to investigate the effects of HOCl on whole muscle function, intracellular Ca2+ handling, and myofilament force production. HOCl exposure significantly decreased maximum specific force in isolated EDL muscles by 26% and 49%, respectively, in C57 and mdx mice (P < 0.0001). In single interosseous fibers, HOCl exposure significantly increased resting intracellular Ca2+ concentration by ∼17–19% (P < 0.05) and decreased the amplitude of electrically induced Ca2+ transients by ∼45% and 50%, respectively, in C57 and mdx fibers (C57, P < 0.05; mdx, P < 0.01). These effects of HOCl on resting Ca2+ could be blocked via application of tetracaine (ryanodine receptor blocker) or Gd3+ (stretch-activated channel blocker; C57, P < 0.01; mdx, P < 0.01 for both). The effect of HOCl on Ca2+ transient amplitude was significantly reduced by Gd3+ (C57, P < 0.05; mdx, P < 0.01). In chemically skinned EDL fibers, HOCl exposure decreased maximum Ca2+-activated force by ∼40% in both C57 and mdx fibers (P < 0.001). These results indicate that HOCl potently affects excitation–contraction coupling via impaired Ca2+ handling and myofilament force production. Hence, HOCl potentially links the chronic inflammation, oxidative stress, and impaired Ca2+ handling that underlies the dystrophic pathology.

Download Full-text

The Influence of Verbal Instruction on Measurement Reliability and Explosive Neuromuscular Performance of the Knee Extensors

Journal of Human Kinetics ◽

10.2478/hukin-2018-0031 ◽

2018 ◽

Vol 65 (1) ◽

pp. 21-34 ◽

Cited By ~ 1

Author(s):

Hamdi Jaafar ◽

Hanene Lajili

Keyword(s):

Muscle Activation ◽

Force Production ◽

Knee Extension ◽

Knee Extensors ◽

Maximal Rate ◽

Measurement Reliability ◽

Verbal Instruction ◽

Electromechanical Delay ◽

Explosive Force ◽

Voluntary Contractions

Abstract The current study aimed to examine the effect of verbal instruction on explosive force production and between-session measurement reliability during maximal voluntary contractions of knee extensors. Following familiarization, 20 healthy males performed 3 maximal contractions with a “hard-and-fast” instruction and 3 maximal contractions with a “fast” instruction during 2 test-retest sessions. Knee extension maximal voluntary force (Fmax) and the maximal rate of force development (RFDmax) were measured. Maximal electromechanical delay (EMDmax), and the maximal rate of muscle activation (RMAmax) of quadriceps muscles were determined. No significant effect of instruction was observed on Fmax (p > 0.05). The RFDmax and RMAmax were significantly higher with the “fast” compared to the “hard-and-fast” instruction (36.07%, ES = 1.99 and 37.24%, ES = 0.92, respectively), whereas EMDmax was significantly lower with the “fast” instruction compared to the “hard-and-fast” instruction (-3.79%, ES = - 0.29). No significant differences between test and retest measurements were found (p < 0.05). However, the reliability of the RFDmax was higher with the fast instruction compared to the hard-and-fast instruction (CV: 7.3 vs. 16.2%; ICC: 0.84 vs. 0.56). Besides, the RFDmax was associated with the RMAmax and EMDmax with a significant effect of instruction. Data showed that the instruction given prior contracting muscle affected explosive force production and associated neuromuscular variables. As a result, the “fast” instruction may be preferred in the assessment of explosive force capacity of skeletal muscle during maximal efforts.

Download Full-text

The relationship between deficit in digit span and genotype in nonsense mutation Duchenne muscular dystrophy

Neurology ◽

10.1212/wnl.0000000000006245 ◽

2018 ◽

Vol 91 (13) ◽

pp. e1215-e1219 ◽

Cited By ~ 4

Author(s):

Mathula Thangarajh ◽

Gary L. Elfring ◽

Panayiota Trifillis ◽

Joseph McIntosh ◽

Stuart W. Peltz ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Cognitive Deficits ◽

Nonsense Mutation ◽

Digit Span ◽

Critical Role ◽

Alternative Promoters ◽

Significant Difference ◽

The Relationship

ObjectiveTo evaluate the relationship between deficit in digit span and genotype in nonsense mutation (nm) Duchenne muscular dystrophy (DMD) (nmDMD).MethodsWe investigated the relationship between normalized digit-span forward (d-sf) and digit-span backward (d-sb) scores to the location of nmDMD mutations in 169 participants ≥5 to ≤20 years who participated in a phase 2b clinical trial. Because alternative promoters are found upstream of DMD exons 30, 45, and 63, we correlated d-sf and d-sb to the specific nmDMD mutation location.ResultsParticipants with nm downstream of exon 30, downstream of exon 45, and downstream of exon 63 had significantly lower normalized d-sf scores (p < 0.0001). Participants with nm downstream of exon 45 in addition had significantly lower normalized d-sb score (p < 0.04). There was no significant difference in the normalized d-sb score in participants with mutations upstream or downstream of DMD exon 30 or upstream or downstream of DMD exon 63.ConclusionOur data provide evidence that specific cognitive deficits correlate to genotype in individuals with nmDMD, highlighting the critical role of brain-specific dystrophin isoforms in the neurobiological manifestations of this disease.Clinicaltrials.gov identifierNCT02090959.

Download Full-text