Capillary muscle

The contraction of a muscle generates a force that decreases when increasing the contraction velocity. This “hyperbolic” force–velocity relationship has been known since the seminal work of A. V. Hill in 1938 [Hill AV (1938) Proc R Soc Lond B Biol Sci 126(843):136–195]. Hill’s heuristic equation is still used, and the sliding-filament theory for the sarcomere [Huxley H, Hanson J (1954) Nature 173(4412):973–976; Huxley AF, Niedergerke R (1954) Nature 173(4412):971–973] suggested how its different parameters can be related to the molecular origin of the force generator [Huxley AF (1957) Prog Biophys Biophys Chem 7:255–318; Deshcherevskiĭ VI (1968) Biofizika 13(5):928–935]. Here, we develop a capillary analog of the sarcomere obeying Hill’s equation and discuss its analogy with muscles.From 1487 to 1516, Leonardo da Vinci planned to write a treatise on human anatomy. The book never appeared, but many drawings and writings have been conserved, mainly at the royal collection at Windsor (1):

After a demonstration of all of the parts of the limbs of man and other animals you will represent the proper method of action of these limbs, that is, in rising after lying down, in moving, running and jumping in various attitudes, in lifting and carrying heavy weights, in throwing things to a distance and in swimming and in every act you will show which limbs and which muscles are the causes of the said actions and especially in the play of the arms. (2, 3)

Apart from Leonardo’s attempts, the understanding of muscle contraction has been a long quest since antiquity and the work of Hippocrates of Cos (4). The topological structure of muscles was described in the anatomical studies by Andreas Vesalius in 1543 (5) and the static force generated was quantified in the first biomechanics treatise of Giovanni Borelli in 1680 (Fig. 1A) (6). One realizes the difficulties associated with the understanding of the force generation mechanism by comparing the scale at which the force is used (typically the body scale: 1?m) to the scale at which the force is generated [contraction of the myosin molecule: 10?nm (7)]. Eight orders of magnitude separate the molecular origin of the force from its macroscopic function, namely the motion of organisms. Considering the scales involved, research on muscles has progressed with the development of new techniques, from early microscopy for the micrometer-scale sarcomere (8), to X-ray diffraction (9) and interference microscopy (10) for the actin–myosin sliding structure, and optical tweezers for the study of individual myosin molecules (7).Open in a separate windowFig. 1.(A) Plate of Borelli’s De Motu Animalium. Figure courtesy of ref. 6. (B) Isotonic lever for human subjects [from Wilkie (11)]. A, hand grip attached to cable; B, catch to hold lever up at the end of movement; C, fixed contact; D, lever with moving contact; E, weight. (C) Force–velocity results obtained with two different subjects: red squares, D.W.; black circles, L.M. The solid lines are Eq. 1, with F₀ = 196?N, v_max = b.F₀/a = 7.5?m/s, and F₀/a = 5 for D.W., and F₀ = 200?N, v_max = 7.0?m/s, and F₀/a = 2.1 for L.M. (data from ref. 11).Despite the complexity of the muscular system, the relation between the force F needed to move a given load and the velocity v of the motion is accessible via macroscopic experiments such as the one from Wilkie sketched in Fig. 1B (11). Here, a constant force F = Mg is imposed by the weight E, and one records the maximal speed of contraction, v(F). Decoupling inertial effects from muscle properties, one gets human muscle characteristics as shown in Fig. 1C. The force reaches its maximum F₀ at v = 0, and it vanishes at a maximal speed v = v_max. The evolution between these two limits is captured by an equation proposed by Hill in 1938 (12), (F + a)(v + b) = (F₀ + a)b, which can be written under the hyperbolic form:FF0=1−v/vmax1+(F0/a)v/vmax.[1]This equation is drawn with a solid line in Fig. 1C for two subjects (D.W. and L.M. in ref. 11), using the values F₀ = 196?N, v_max = bF₀/a = 7.5?m/s, and F₀/a = 5 for D.W., and F₀ = 200?N, v_max = 7.0?m/s, and F₀/a = 2.1 for L.M. The isometric tension F₀ defines the force against which the muscle neither shortens nor lengthens, and v_max is the maximal speed reached without load (F = 0). These results illustrate the accuracy of Hill’s equation and the variability of the parameter F₀/a between different subjects. Apart from skeletal human muscles, Hill’s equation (Eq. 1) is found to apply to almost all muscle types and over various species (13).The contractile muscular machinery is made of parallel muscle cells that extend from one tendon to another, which connect to bones. A muscle cell is composed of nuclei and myofibrils, a linear assembly of sarcomeres, the elementary contractile unit. The typical size of sarcomeres is 3 μm, so that their number in myofibril of a 30-cm muscle cell is on the order of 10⁵. A sarcomere itself is made of thin actin filaments connected to thick myosin filaments via myosin heads (Fig. 2 C1 and C2). When a neuron stimulates a muscle cell, an action potential sweeps over the plasma membrane of the muscle cell. The action potential releases internal stores of calcium that flow through the muscle cell and trigger a contraction (C2). Actin and myosin filaments are juxtaposed but cannot interact in the absence of calcium (relaxed-state C1). With calcium, the myosin-binding sites are open on the actin filaments, and ATP makes the myosin motors crawl along the actin, resulting in a contraction of the muscle fiber (C2) (14, 15). The interaction energy increases with the number of cross-bridges, namely with the surface between actin and myosin threads.Open in a separate windowFig. 2.Experimental setup of a capillary muscle and its biological inspiration, the sarcomere. The steel wire is equivalent to the myosin filament that slides in the silicone oil tube, which stands for the actin filament. (A) Position at t = 0, corresponding to relaxed state of the sarcomere (C1). (B) Position at t > 0, corresponding to the contracted state of the sarcomere (C2). (D) Example of capillary contraction obtained with 2r = 1.8?mm, 2R = 5?mm, η = 1 Pa⋅s, γ = 22 mN/m, k = 3.3 μN/m, and x₀ = 7.6?mm.Hill’s equation is a heuristic law and its connection to the sliding-filament model has first been established via adjustable correlations (16) and later via strong theoretical assumptions (17). The purpose of the present article is to build a capillary analog of the sliding-filament model, to record the corresponding force–velocity relationship, and to show how this minimal model system leads to Hill’s equation.     

Associations of muscle stiffness and thickness with muscle strength and muscle power in elderly women

Aim: The aims of this study were to investigate the influence of age on muscle stiffness and to examine the relationships among muscle stiffness, muscle thickness, subcutaneous fat thickness, muscle strength and muscle power in elderly women. Methods: The subjects were 16 young (mean age 20.3 years) and 34 elderly (mean age 84.2 years) women. Muscle stiffness of the right quadriceps femoris muscle was measured at rest and during a maximal voluntary isometric muscle contraction using a myotonometer, a computerized, electronic tissue compliance meter. Thicknesses of the rectus femoris and the vastus intermedius muscles and the overlying subcutaneous fat were measured using ultrasound. Quadriceps strength and the chair stand test were used to represent muscle strength and muscle power, respectively. Results: There were significant differences in muscle stiffness between rest and contraction conditions among the young but not the elderly women. Muscle stiffness during contraction, the rate of change in muscle stiffness during contraction, and muscle thickness were significantly greater in young than in elderly subjects. Pearson correlation coefficient analyses showed that muscle stiffness was significantly associated with muscle power, but not with muscle strength. Conclusion: This study suggests that the increase in muscle stiffness during voluntary muscle contraction is limited in elderly women compared with young women, and that muscle stiffness may be related to muscle power rather than muscle strength in elderly persons. Geriatr Gerontol Int 2012; 12: 86–92.     

An invertebrate smooth muscle with striated muscle myosin filaments

Muscle tissues are classically divided into two major types, depending on the presence or absence of striations. In striated muscles, the actin filaments are anchored at Z-lines and the myosin and actin filaments are in register, whereas in smooth muscles, the actin filaments are attached to dense bodies and the myosin and actin filaments are out of register. The structure of the filaments in smooth muscles is also different from that in striated muscles. Here we have studied the structure of myosin filaments from the smooth muscles of the human parasite Schistosoma mansoni. We find, surprisingly, that they are indistinguishable from those in an arthropod striated muscle. This structural similarity is supported by sequence comparison between the schistosome myosin II heavy chain and known striated muscle myosins. In contrast, the actin filaments of schistosomes are similar to those of smooth muscles, lacking troponin-dependent regulation. We conclude that schistosome muscles are hybrids, containing striated muscle-like myosin filaments and smooth muscle-like actin filaments in a smooth muscle architecture. This surprising finding has broad significance for understanding how muscles are built and how they evolved, and challenges the paradigm that smooth and striated muscles always have distinctly different components.The muscles of animals are of two basic types: striated or smooth. The presence or absence of striations depends on whether or not the thick (myosin) and thin (actin) filaments are in longitudinal register (1). In striated muscles, thin filaments of similar lengths are aligned via their attachment to transversely arranged Z-lines, which form the boundaries of the contractile unit, called the sarcomere. Thick filaments, also of similar lengths and in register, lie midway between the Z-lines (1). The repeating pattern of sarcomeres joined end-to-end gives rise to the striations seen in the light microscope (2). Smooth muscles, in contrast, lack both Z-lines and aligned, uniform-length thick and thin filaments; striations are therefore absent, creating a “smooth” appearance in the light microscope. In these muscles the Z-lines are replaced by narrower dense bodies, which act as attachment sites for thin filaments (3). In most animals, striated muscles are specialized for rapid, precisely controlled movements, whereas smooth muscles are used for slow or sustained contraction (1, 3). Within these broad categories there is considerable diversity in structure and function across species. Thus, striated muscles may be cross-striated (vertebrates and invertebrates) or obliquely/helically striated (invertebrates only) (4, 5), and smooth muscles may have relatively short (vertebrates and many invertebrates) or very long (molluscan) myosin filaments (6).Our knowledge of the molecular structure and function of smooth muscle, and how this contrasts with striated muscle, has come mostly from studies of vertebrates. Several key differences are found: (i) The striated muscle myosin II heavy chain (MHC II) has key sites of sequence conservation in the tail and head, which clearly distinguish it from smooth and nonmuscle myosin II sequences (7, 8). (ii) Striated muscles are regulated via Ca²⁺ binding to troponin on the thin filaments (9), whereas smooth muscles lack troponin and are regulated by Ca²⁺-induced phosphorylation of the myosin regulatory light chains (10). (iii) The thick filaments in striated muscles have a helical, bipolar structure, in which the polarity of myosin molecules reverses midway along the filament length, whereas smooth muscle thick filaments are nonhelical and side-polar, with oppositely oriented myosin molecules on opposite sides of the filament along its entire length (11, 12). Whether comparable differences occur in invertebrate muscle has been little studied, with the exception of molluscan smooth muscles, which have giant thick filaments (containing high levels of paramyosin) that are specialized to function in the long-lived, high-tension “catch” state (13).Here we have studied the molecular structure and function of the muscles of the parasitic flatworm Schistosoma mansoni, which is responsible for the tropical disease schistosomiasis, affecting 200 million people worldwide (14). Our interest in these muscles was catalyzed by reports that the drug used to treat schistosomiasis (praziquantel) may act on the myosin molecule (15), and that muscle proteins like myosin, paramyosin, and certain regions of actin might be useful targets for the development of an antischistosomal vaccine or chemotherapy (16–18). We show that the adult form of S. mansoni has exclusively smooth muscles, and yet its thick filaments have the bipolar, helical structure characteristic of striated muscle filaments from other invertebrates. This similarity in thick filament structure is supported by sequence analysis, which groups the schistosome MHC II with other striated muscle myosin sequences, not with their smooth/nonmuscle counterparts. Whereas the thick filaments of schistosome smooth muscles have striated muscle characteristics, their thin filaments appear to lack troponin and are not regulated by Ca²⁺; they are thus similar to other smooth muscle thin filaments. We conclude that, in contrast to vertebrates, schistosome smooth muscles are hybrids, incorporating proteins and filament structures from both smooth and striated muscles.     

Respiratory muscle fatigue

Respiratory muscle fatigue is caused by excessive effort relative to the strength and endurance of the respiratory muscles. It can be manifested by reductions in respiratory drive (central fatigue), by impaired neuromuscular transmission (transmission fatigue), by decreased contractility (contractile fatigue), or by a combination of these factors. Respiratory muscle fatigue probably contributes to the difficulties some patients have with weaning from mechanical ventilation, the symptoms of exercise intolerance and dyspnea in chronic lung disease, and CO2 retention. Therapy depends on a reduction in the required level of respiratory effort and/or an improvement in respiratory muscle strength and endurance.     

Age-related muscle dysfunction

Aging is associated with a progressive decline of muscle mass, strength, and quality, a condition described as sarcopenia of aging. Despite the significance of skeletal muscle atrophy, the mechanisms responsible for the deterioration of muscle performance are only partially understood. The purpose of this review is to highlight cellular, molecular, and biochemical changes that contribute to age-related muscle dysfunction.     

Tracheal smooth muscle

Contraction of tracheal smooth muscle requires the binding of Ca2+ to calmodulin, which then binds to and activates MLCK. The Ca2+-calmodulin-MLCK complex catalyzes the phosphorylation of myosin, which causes contraction by stimulating actin-activated Mg2+-ATPase activity of myosin. Myosin phosphorylation appears to be a transient event that is responsible for a high velocity of shortening. The mechanism responsible for maintenance of isometric force is unknown, although a second Ca2+-dependent mechanism with a greater sensitivity to Ca2+ than the activation of MLCK has been hypothesized. Force would be maintained through the slow cycling of nonphosphorylated cross-bridges or a small population of phosphorylated cross-bridges. Tracheal smooth muscle utilizes both extracellular and intracellular pools of Ca2+ for contraction. Moreover, the membrane channels through which extracellular Ca2+ passes have been subdivided into potential-dependent channels (PDCs) and receptor-operated channels (ROCs) independent of membrane potential. The relative extent to which extracellular and intracellular sources of Ca2+ as well as PDCs and ROCs are utilized depends on the agonist used for contraction, its concentration, and the type and location of the smooth muscle being investigated. Calcium antagonists such as verapamil and nifedipine, which reportedly block PDCs but not ROCs, are much better inhibitors of tracheal smooth muscle contractions induced by serotonin than those induced by acetylcholine, histamine, and leukotriene D4, indicating an effect of these latter three agents on ROCs. Relaxation of tracheal smooth muscle following stimulation of beta-adrenergic receptors most likely results from an increase in cAMP that stimulates a cAMP-dependent protein kinase to catalyze a protein phosphorylation that leads to relaxation by decreasing the intracellular concentration of Ca2+. The primary mechanisms whereby cAMP is thought to reduce intracellular Ca2+ to effect relaxation include: activation of a calmodulin-sensitive Ca2+ ATPase in the plasma and sarcoplasmic reticulum membranes, and extrusion of Ca2+ by a Na+-Ca2+ exchange mechanism coupled to Na+-K+-ATPase in the cell membrane. A more controversial mechanism for relaxation that bypasses Ca2+ might involve the dephosphorylation of myosin. Leukotrienes are released by various stimuli, including immunologic challenge, and have been considered as important mediators of bronchoconstriction in allergic asthma.(ABSTRACT TRUNCATED AT 400 WORDS)     

Diabetic muscle necrosis

We report on the case of a patient with diabetic myonecrosis. We remind clinicians of this underdiagnosed condition and discuss the pathophysiology, diagnosis, management, and prognosis of this disabling condition.     

Paraneoplastic muscle disease

In paraneoplastic muscle disease, the malignancy may remotely affect neuromuscular transmission or incite muscle inflammation or necrosis. In several of these diseases, an autoimmune basis for the muscle disease has been established and has become a defining feature. These paraneoplastic muscle diseases may be the first manifestation of a malignancy, and their diagnosis thus demands a vigilant search for an underlying tumor. This article is focused on inflammatory and necrotizing myopathies and disorders of neuromuscular transmission that may arise in the setting of malignancy and are considered paraneoplastic phenomena.     

Papillary muscle rupture

We report a not previously described complication in a retrograde transcatheter aortic valve implantation procedure: A fatal rupture of a papillary muscle producing massive regurgitation. We found papillary muscle head calcification as an anatomical substrate that could facilitate this complication.© 2011 Wiley‐Liss, Inc.     

Abnormalities in muscle density and muscle function in hypophosphatemic rickets

Context: Animal studies suggest that hypophosphatemic rickets (HPR) is associated with muscle function deficits, but it is unknown whether humans with HPR have a muscle disorder. Objective: Our objective was to assess calf muscle size and density (an indicator of muscle quality) and lower extremity muscle function in patients with HPR. Setting: The study was carried out in the outpatient department of a pediatric orthopedic hospital. Patients and Other Participants: Participants included 34 individuals with HPR (6-60 yr; nine males) and 34 age- and gender-matched controls. Main Outcome Measures: Calf muscle parameters (muscle cross-sectional area and density) were measured by peripheral quantitative computed tomography. Lower extremity muscle function (peak force per body weight and peak power per body mass) was measured by jumping mechanography through five tests with different levels of difficulty: multiple two-legged hopping, multiple one-legged hopping, single two-legged jump, chair-rise test, and heel-rise test. Results: Compared with age- and gender-matched controls, patients with HPR had normal muscle size (P = 0.58) but lower muscle density (P = 0.008) and lower peak muscle force and power (P < 0.001 in each test). Muscle function tests were also lower in the subgroup of patients with straight legs (n = 13) than in controls, even though patients with straight legs had higher muscle function test results than patients with severe leg deformities. Conclusions: The present study suggests that muscle weakness is a clinical feature of HPR. Lower muscle quality and limb deformities contribute to this functional deficit.     

Skeletal muscle characteristics, muscle strength and thigh muscle area in patients before and after cardiac transplantation

BACKGROUND: Patients with chronic heart failure demonstrate several skeletal muscle abnormalities. The underlying mechanisms are unclear. After cardiac transplantation, cardiac function is restored, but exercise capacity is still impaired. AIM: To evaluate the influence of cardiac transplantation on skeletal muscle fibre composition, fibre area and capillarization as well as muscle enzymes, lactate, thigh muscle area and strength. METHODS: Ten patients were longitudinally investigated before, 1-3 and 6-9 months after transplantation. Ten healthy individuals served as controls. A biopsy from the lateral vastus muscle was obtained and the thigh muscle area was measured with computed tomography. Muscle strength in the knee extensors and exercise capacity were also evaluated. RESULTS: Muscle lactate was elevated in patients vs. controls (3.6+/-3.0 vs. 1.5+/-0.7 mmol/kg wet wt., P=0.037), and decreased to normal (1.4+/-0.3 mmol/kg wet wt., P=0.038) after transplantation. Citrate synthase activity was decreased in patients (5.6+/-1.5 micromol/g wet wt./min) vs. controls (8.1+/-1.6 micromol/g wet wt./min, P=0.0018), and did not change post transplantation. Patients had decreased number of capillaries in contact with each fibre vs. controls (2.6+/-0.5 vs. 3.5+/-1.0, P=0.039) which persisted post transplantation. Exercise capacity increased after transplantation (74+/-22 vs. 118+/-26 W, P=0.0002), whereas muscle strength did not improve significantly. CONCLUSION: The persisting intrinsic abnormalities in skeletal muscle after cardiac transplantation may contribute to the impaired exercise capacity observed in cardiac transplant recipients.     

Airway smooth muscle

The greatest impetus to research in elucidating the fundamental biophysics and biochemistry of airway smooth muscle (ASM) has undoubtedly been provided by the need to understand how these are altered in asthma. Many of the biophysical and biochemical properties of this muscle have been reviewed before (Stephens, 1970; Stephens, 1977; Mulvaney, 1979; Souhrada and Loader, 1979; Stephens and Kroeger, 1980). They resemble those of striated muscle; however, even though mechanical properties are very similar, there are differences in biochemistry. For example, in smooth muscle, calcium-sensitive regulation of contraction is mediated by a calmodulin/myosin-light-chain kinase/phosphatase system, not by the familiar troponin-tropomyosin system (Gorecka et al., 1974; Mrwa and Ruegg, 1975; Dillon et al., 1981; Aksoy et al., 1982). Thus, the molecular mechanisms to be investigated in understanding disorders of increased smooth muscle contraction, which occur in allergic bronchospasm (Souhrada and Dickey, 1976), for example, may be quite different from those in striated muscle. Much of the following material is based on studies of canine tracheal smooth muscle (TSM) because there is evidence (Jenne et al., 1975) that it serves as a model for ASM-at least with respect to contractility down to the sixth generation of airways. Studies of isolated smooth muscle from smaller airways (Russell, 1978) are few and are based mainly on studies of lung strips (Lulich et al., 1976). Since then, we have developed a bronchial smooth muscle preparation (fifth generation) that allows precise study of those airways that are involved in allergic bronchospasm. Considerable work has been carried out on ASM from a variety of animal models of asthma. It should be pointed out that none of these reproduces the human disease exactly, and that they really should be identified as examples of nonspecific hyperreactivity. Be that as it may, the nonspecificity found in human patients in vivo and in animals (Peterson et al., 1971; Hargreave et al., 1980) suggests that the primary cause of asthma may reside at the muscle cell level. Whether it is the cell membrane, the excitation-contraction coupling apparatus, or the contractile machinery that is primarily involved, is not yet known with certainty.