Cardiac myosin filaments are directly regulated by calcium
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Ma, Weikang↗
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Characterisation of motor cortex organisation in patients with different presentations of persistent low back pain
Abstract Persistence of low back pain is thought to be associated with different underlying pain mechanisms, including ongoing nociceptive input and central sensitisation. We hypothesised that primary motor cortex (M1) representations of back muscles (a measure of motor system adaptation) would differ between pain mechanisms, with more consistent observations in individuals presumed to have an ongoing contribution of nociceptive input consistently related to movement/posture. We tested 28 participants with low back pain sub‐grouped by the presumed underlying pain mechanisms: nociceptive pain, nociplastic pain and a mixed group with features consistent with both. Transcranial magnetic stimulation was used to study M1 organisation of back muscles. M1 maps of multifidus (deep and superficial) and longissimus erector spinae were recorded with fine‐wire electromyography and thoracic erector spinae with surface electromyography. The nociplastic pain group had greater variability in M1 map location (centre of gravity) than other groups ( p < .01), which may suggest less consistency, and perhaps relevance, of motor cortex adaptation for that group. The mixed group had greater overlap of M1 representations between deep/superficial muscles than nociceptive pain (deep multifidus/longissimus: p = .001, deep multifidus/thoracic erector spinae: p = .008) and nociplastic pain (deep multifidus/longissimus: p = .02, deep multifidus/thoracic erector spinae: p = .02) groups. This study provides preliminary evidence of differences in M1 organisation in subgroups of low back pain classified by likely underlying pain mechanisms. Despite the sample size, differences in cortical re‐organisation between subgroups were detected. Differences in M1 organisation in subgroups of low back pain supports tailoring of treatment based on pain mechanism and motor adaptation.
Elgueta‐Cancino, Edith↗
A GPU based high-resolution multilevel biomechanical head and neck model for validating deformable image registration
Purpose: Validating the usage of deformable image registration (DIR) for daily patient positioning is critical for adaptive radiotherapy (RT) applications pertaining to head and neck (HN) radiotherapy. The authors present a methodology for generating biomechanically realistic ground-truth data for validating DIR algorithms for HN anatomy by (a) developing a high-resolution deformable biomechanical HN model from a planning CT, (b) simulating deformations for a range of interfraction posture changes and physiological regression, and (c) generating subsequent CT images representing the deformed anatomy. Methods: The biomechanical model was developed using HN kVCT datasets and the corresponding structure contours. The voxels inside a given 3D contour boundary were clustered using a graphics processing unit (GPU) based algorithm that accounted for inconsistencies and gaps in the boundary to form a volumetric structure. While the bony anatomy was modeled as rigid body, the muscle and soft tissue structures were modeled as mass–spring-damper models with elastic material properties that corresponded to the underlying contoured anatomies. Within a given muscle structure, the voxels were classified using a uniform grid and a normalized mass was assigned to each voxel based on its Hounsfield number. The soft tissue deformation for a given skeletal actuation was performed using an implicit Euler integration with each iteration split into two substeps: one for the muscle structures and the other for the remaining soft tissues. Posture changes were simulated by articulating the skeletal structure and enabling the soft structures to deform accordingly. Physiological changes representing tumor regression were simulated by reducing the target volume and enabling the surrounding soft structures to deform accordingly. Finally, the authors also discuss a new approach to generate kVCT images representing the deformed anatomy that accounts for gaps and antialiasing artifacts that may be caused by the biomechanical deformation process. Accuracy and stability of the model response were validated using ground-truth simulations representing soft tissue behavior under local and global deformations. Numerical accuracy of the HN deformations was analyzed by applying nonrigid skeletal transformations acquired from interfraction kVCT images to the model’s skeletal structures and comparing the subsequent soft tissue deformations of the model with the clinical anatomy. Results: The GPU based framework enabled the model deformation to be performed at 60 frames/s, facilitating simulations of posture changes and physiological regressions at interactive speeds. The soft tissue response was accurate with a R{sup 2} value of >0.98 when compared to ground-truth global and local force deformation analysis. The deformation of the HN anatomy by the model agreed with the clinically observed deformations with an average correlation coefficient of 0.956. For a clinically relevant range of posture and physiological changes, the model deformations stabilized with an uncertainty of less than 0.01 mm. Conclusions: Documenting dose delivery for HN radiotherapy is essential accounting for posture and physiological changes. The biomechanical model discussed in this paper was able to deform in real-time, allowing interactive simulations and visualization of such changes. The model would allow patient specific validations of the DIR method and has the potential to be a significant aid in adaptive radiotherapy techniques.
60 APPLIED LIFE SCIENCES↗
Pharmacologic or genetic interference with atrogene signaling protects against glucocorticoid-induced musculoskeletal and cardiac disease
Despite their beneficial actions as immunosuppressants, glucocorticoids (GC) have devastating effects on the musculoskeletal and cardiac systems, as long-term treated patients exhibit high incidence of falls, bone fractures, and cardiovascular events. Herein, we show that GC upregulate simultaneously in bone, skeletal muscle, and the heart the expression of E3 ubiquitin ligases (atrogenes), known to stimulate the proteasomal degradation of proteins. Activation of vitamin D receptor (VDR) signaling with the VDR ligands calcitriol or eldecalcitol prevented GC-induced atrogene upregulation in vivo and ex vivo in bone/muscle organ cultures and preserved tissue structure/mass and function of the 3 tissues in vivo. Direct pharmacologic inhibition of the proteasome with carfilzomib also conferred musculoskeletal protection. Genetic loss of the atrogene MuRF1-mediated protein ubiquitination in ΔRING mice afforded temporary or sustained protection from GC excess in bone or skeletal and heart muscle. We concluded that the atrogene pathway downstream of MuRF1 underlies GC action in bone, muscle, and the heart, and it can be pharmacologically or genetically targeted to confer protection against the damaging actions of GC simultaneously in the 3 tissues.
Research & Experimental Medicine↗
Exogenous erythropoietin increases hematological status, fat oxidation, and aerobic performance in males following prolonged strenuous training
Abstract This study investigated the effects of EPO on hemoglobin (Hgb) and hematocrit (Hct), time trial (TT) performance, substrate oxidation, and skeletal muscle phenotype throughout 28 days of strenuous exercise. Eight males completed this longitudinal controlled exercise and feeding study using EPO (50 IU/kg body mass) 3×/week for 28 days. Hgb, Hct, and TT performance were assessed PRE and on Days 7, 14, 21, and 27 of EPO. Rested/fasted muscle obtained PRE and POST EPO were analyzed for gene expression, protein signaling, fiber type, and capillarization. Substrate oxidation and glucose turnover were assessed during 90‐min of treadmill load carriage (LC; 30% body mass; 55 ± 5% V̇O 2 peak) exercise using indirect calorimetry, and 6‐6‐[ 2 H 2 ]‐glucose PRE and POST. Hgb and Hct increased, and TT performance improved on Days 21 and 27 compared to PRE ( p < 0.05). Energy expenditure, fat oxidation, and metabolic clearance rate during LC increased ( p < 0.05) from PRE to POST. Myofiber type, protein markers of mitochondrial biogenesis, and capillarization were unchanged PRE to POST. Transcriptional regulation of mitochondrial activity and fat metabolism increased from PRE to POST ( p < 0.05). These data indicate EPO administration during 28 days of strenuous exercise can enhance aerobic performance through improved oxygen carrying capacity, whole‐body and skeletal muscle fat metabolism.
Drummer, Devin J.↗
EMD-57033 Augments the Contractility in Porcine Myocardium by Promoting the Activation of Myosin in Thick Filaments
Sufficient cardiac contractility is necessary to ensure the sufficient cardiac output to provide an adequate end-organ perfusion. Inadequate cardiac output and the diminished perfusion of vital organs from depressed myocardium contractility is a hallmark end-stage of heart failure. There are no available therapeutics that directly target contractile proteins to improve the myocardium contractility and reduce mortality. The purpose of this study is to present a proof of concept to aid in the development of muscle activators (myotropes) for augmenting the contractility in clinical heart failure. Here we use a combination of cardiomyocyte mechanics, the biochemical quantification of the ATP turnover, and small angle X-ray diffraction on a permeabilized porcine myocardium to study the mechanisms of EMD-57033 (EMD) for activating myosin. We show that EMD increases the contractility in a porcine myocardium at submaximal and systolic calcium concentrations. Biochemical assays show that EMD decreases the proportion of myosin heads in the energy sparing super-relaxed (SRX) state under relaxing conditions, which are less likely to interact with actin during contraction. Structural assays show that EMD moves the myosin heads in relaxed muscles from a structurally ordered state close to the thick filament backbone, to a disordered state closer to the actin filament, while simultaneously inducing structural changes in the troponin complex on the actin filament. The dual effects of EMD on activating myosin heads and the troponin complex provides a proof of concept for the use of small molecule muscle activators for augmenting the contractility in heart failure.
59 BASIC BIOLOGICAL SCIENCES↗
Effect of High-Protein Diets on Integrated Myofibrillar Protein Synthesis before Anterior Cruciate Ligament Reconstruction: A Randomized Controlled Pilot Study
Increasing dietary protein intake during periods of muscle disuse may mitigate the resulting decline in muscle protein synthesis (MPS). The purpose of this randomized pilot study was to determine the effect of increased protein intake during periods of disuse before anterior cruciate ligament (ACL) reconstruction on myofibrillar protein synthesis (MyoPS), and proteolytic and myogenic gene expression. Six healthy, young males (30 ± 9 y) were randomized to consume a high-quality, optimal protein diet (OP; 1.9 g·kg−1·d−1) or adequate protein diet (AP; 1.2 g·kg−1·d−1) for two weeks before ACL reconstruction. Muscle biopsies collected during surgery were used to measure integrated MyoPS during the intervention (via daily deuterium oxide ingestion) and gene expression at the time of surgery. MyoPS tended to be higher, with a large effect size in OP compared to AP (0.71 ± 0.1 and 0.54 ± 0.1%·d−1; p = 0.076; g = 1.56). Markers of proteolysis and myogenesis were not different between groups (p > 0.05); however, participants with greater MyoPS exhibited lower levels of MuRF1 gene expression compared to those with lower MyoPS (r = −0.82, p = 0.047). The data from this pilot study reveal a potential stimulatory effect of increased daily protein intake on MyoPS during injury-mediated disuse conditions that warrants further investigation.
Howard, Emily E. (ORCID:0000000179791236)↗
Separate physiological roles for two isozymes of pyridine nucleotide-linked glycerol-3-phosphate dehydrogenase in chicken.
The isozymes considered are designated 'liver type' and 'muscle type' based on the tissue of highest concentration. Electrophoretic analysis shows that the liver type is found in small amounts or is undetectable in all tissues studied except liver. The muscle type is found in skeletal muscles and kidney. Presumptive hybrid enzymes occur at low levels in chicken liver and kidney. The tissue distribution of glyceron-3-P dehydrogenase in several birds capable of sustained flight is different than in chicken.
White, H. B., III↗
Changes in sulfhydryl groups of honeybee glyceraldehyde phosphate dehydrogenase associated with generation of the intermediate plateau in its saturation kinetics
Honeybee and rabbit muscle GPDH were studied to obtain information at the chemical level regarding anomolous saturation kinetics of the honeybee enzyme. Results demonstrate that the enzyme's sulfhydryl groups are implicated in the process. Measured by DTNB titration, native honeybee GPDH has one less active SH than the native rabbit muscle enzyme and displays changes in overall sulfhydryl reactivity after preincubation with G-3-P or G-3-P plus NAD+. The total DTNB reactive sulfhydryls of rabbit muscle GPDH are not changed by preincubation with NAD+ or G-3-P; honeybee GPDH, under certain conductions of preincubation with these ligands, shows a decrease of two total DTNB reactive SH groups. This difference has been confirmed by an independent experiment in which the two enzymes were carboxymethylated with C-14 bromoacetic acid.
Gelb, W. G.↗
Cardiac mechanics: Physiological, clinical, and mathematical considerations
Recent studies concerning the basic physiological and biochemical principles underlying cardiac muscle contraction, methods for the assessment of cardiac function in the clinical situation, and mathematical approaches to cardiac mechanics are presented. Some of the topics covered include: cardiac ultrastructure and function in the normal and failing heart, myocardial energetics, clinical applications of angiocardiography, use of echocardiography for evaluating cardiac performance, systolic time intervals in the noninvasive assessment of left ventricular performance in man, evaluation of passive elastic stiffness for the left ventricle and isolated heart muscle, a conceptual model of myocardial infarction and cardiogenic shock, application of Huxley's sliding-filament theory to the mechanics of normal and hypertrophied cardiac muscle, and a rheological modeling of the intact left ventricle. Individual items are announced in this issue.
Mirsky, I.↗
Regional measurement of body nitrogen
Studies of methods for determining changes in the muscle mass of arms and legs are described. N-13 measurements were made in phantom and cadaver parts after neutron irradiation. The reproducibility in these measurements was found to be excellent and the radiation dose required to provide sufficient activation was determined. Potassium-40 measurements were made on persons who lost muscle mass due to leg injuries. It appears that K-40 measurements may provide the most accurate and convenient method for determining muscle mass changes.
Palmer, H. E.↗
Muscular deconditioning and its prevention in space flight
Exercise and exercise devices on Skylab missions prevented muscle loss in spacecrews. It is concluded that muscle in space is no different from muscle on earth; if it is properly nourished and exercised at reasonable load levels, it maintains its function under weightlessness conditions.
Thornton, W. E.↗
Isokinetic exercise: A review of the literature
Isokinetic muscle training has all the advantages of isometrics and isotonics while minimizing their deficiencies. By holding the speed of movement constant throughout the full range of motion, isokinetic training devices respond with increased resistance rather than acceleration when the power output of the muscle is increased. Isokinetic training is superior to isometric and isotonic training with respect to increases in strength, specificity of training, desirable changes in motor performance tasks, lack of muscle soreness, and decreases in relative body fat.
Olree, H. D.↗
Influence of hypokinesis on physiological functions in fowl
The effects of hypokinesis and postincubation stress (which are characteristic for modern techniques of poultry cage keeping) on the endocrine functions, metabolic reactions, body weight growth and proteosynthesis in the muscle of cocks was investigated. The stress due to hypokinesis was observed in growing cocks housed in metallic cages in which they could hardly turn around. The findings obtained indicate that a 35-day hypokinesis did not exert any more significant influence both on physiological functions and body weight growth as well as on proteosynthesis in the muscle of cocks under study; however, it speeded up the protein metabolism in the muscle. The postincubation stress modified significantly the hypokinesis effect. Findings recorded in birds differed considerably from findings obtained in laboratory mammals, in which the hypokinesis induced significant changes in endocrine functions, body weight decrease and proteosynthesis disorders. A good tolerance of hypokinesis by fowl can be interpreted not only by the phylogenetic remoteness of the compared species but also by the domestication.
Nvota, J.↗
Antibodies to myofibril antigens in cosmonauts after spaceflights
Serum samples obtained from 15 astronauts before and after spaceflights were studied with the use of the indirect immunofluorescent method. In seven astronauts antibodies to different elements of the human heart muscle appeared after flights. Strong and very strong luminescence of the elements of heart muscle tissue was detected in the astronauts after the third space flight. In a study of the sera on sections of bovine heart muscle tissue the reactions of the sera taken before and after flight were found to show no essential differences.
Tashpulatov, R. Y.↗
Suspension restraint - Induced hypokinesia and antiorthostasis as a simulation of weightlessness
Muscle, renal, fluid and electrolyte responses were measured in suspended rats; the hind limbs are non-load bearing and the front limbs can be used for feeding and grooming. Hind limb hypokinesia reverses after removal from the suspension harness. This suspension system is adjustable for a head-down tilt to produce antiorthostatic responses which are also reversible. Responses to hypokinesia or antiorthostatic hypokinesia for up to 14 days were measured, e.g., muscle atrophy: soleus greater than gastrocnemius equals plantaris greater than extensor digitorum longus, kaliuresis, and increased excretion of urea, NH3, and 3 methylhistidine. Muscle protein loss, a response to a reduction in RNA, is also reversible. A head-down tilt for 7-14 days results in diuresis and natriuresis. These changes are reversed within 24 hours after removal from the restraint harness. Physiological effects of suspension restraint can be used to simulate and predict responses to microgravity exposure.
Musacchia, X. J.↗
Fluid shifts in vascular and extravascular compartments of humans during and after simulated weightlessness
A study is presented of the transcapillary pressures and the possible fluid shifts in muscles and subcutaneous tissue of the lower leg before, during, and after head-down tilt. Results showed that the subjects experienced facial edema, headache, nasal congestion, diuresis, and decreased lower-leg volume in response to 8 hours of 5 degree head-down tilt. Also found were significant decreases in systolic and diastolic pressures 2 hours after initiation of tilt, although blood pressure normalized thereafter. The lower-leg volume, urine output and interstitial fluid pressures of the tibialis anterior muscle and overlying subcutaneous tissue also changed significantly. No significant change was found in the colloid osmotic pressures of blood or interstitial fluid. It is concluded that these results indicate the need for countermeasures to maintain precapillary-muscle tone during long space flights in order to prevent swelling of lower-leg tissues upon readjustment to earth's gravity.
Hargens, A. R.↗
Handgrip and general muscular strength and endurance during prolonged bedrest with isometric and isotonic leg exercise training
Measurements of maximal grip strength and endurance at 40 percent max strength were obtained for 7 men 19-21 years of age, 1-2 days before and on the first recovery day during three 2-week bedrest (BR) periods, each separated by a 3-week ambulatory recovery period. The subjects performed isometric exercise (IME) for 1 hr/day, isotonic exercise (ITE) for 1 hr/day, and no exercise (NOE) in the three BR periods. It was found that the mean maximal grip strength was unchanged after all three BR periods. Mean grip endurance was found to be unchanged after IME and ITE training, but was significantly reduced after NOE. These results indicate that IME and ITE training during BR do not increase or decrease maximal grip strength, alghough they prevent loss of grip endurance, while the maximal strength of all other major muscle groups decreases in proportion to the length of BR to 70 days. The maximal strength reduction of the large muscle groups was found to be about twice that of the small muscle groups during BR. In addition, it is shown that changes in maximal strength after spaceflight, BR, or water immersion deconditioning cannot be predicted from changes in submaximal or maximal oxygen uptake values.
Greenleaf, J. E.↗