How Muscles Function - The Work Loop Technique

Anna Ahn discusses Bob Josephson’s 1985 paper entitled: ‘Mechanical power output from striated muscle during cyclic contraction’

A Motor and a Brake: Two Leg Extensor Muscles Acting at the Same Joint Manage Energy Differently in a Running Insect

The individual muscles of a multiple muscle group at a given joint are often assumed to function synergistically to share the load during locomotion. We examined two leg extensors of a running cockroach to test the hypothesis that leg muscles within an anatomical muscle group necessarily manage (i.e. produce, store, transmit or absorb) energy similarly during running. Using electromyographic and video motion-analysis techniques, we determined that muscles 177c and 179 are both active during the first half of the stance period during muscle shortening. Using the in vivo strain and stimulation patterns determined during running, we measured muscle power output. Although both muscles were stimulated during the first half of shortening, muscle 177c generated mechanical energy (28 W kg–1) like a motor, while muscle 179 absorbed energy (–19 W kg–1) like a brake. Both muscles exhibited nearly identical intrinsic characteristics including similar twitch kinetics and force–velocity relationships. Differences in the extrinsic factors of activation and relative shortening velocity caused the muscles to operate very differently during running. Presumed redundancy in a multiple muscle group may, therefore, represent diversity in muscle function. Discovering how muscles manage energy during behavior requires the measurement of a large number of dynamically interacting variables

Static Forces and Moments Generated in the Insect Leg: Comparison of a Three-Dimensional Musculo-Skeletal Computer Model With Experimental Measurements

As a first step towards the integration of information on neural control, biomechanics and isolated muscle function, we constructed a three-dimensional musculo-skeletal model of the hind leg of the death-head cockroach Blaberus discoidalis. We tested the model by measuring the maximum force generated in vivo by the hind leg of the cockroach, the coxa-femur joint angle and the position of this leg during a behavior, wedging, that was likely to require maximum torque or moment production. The product of the maximum force of the leg and its moment arm yielded a measured coxa-femur joint moment for wedging behavior. The maximum musculo-apodeme moment predicted by summing all extensor muscle moments in the model was adequate to explain the magnitude of the coxa-femur joint moment produced in vivo by the cockroach and occurred at the same joint angle measured during wedging. Active isometric muscle forces predicted from our model varied by 3.5-fold among muscles and by as much as 70% with joint angle. Sums of active and passive forces varied by less than 3.5% over the entire range of possible joint angles (0-125º). Maximum musculo-apodeme moment arms varied nearly twofold among muscles. Moment arm lengths decreased to zero and switched to the opposite side of the center of rotation at joint angles within the normal range of motion. At large joint angles (\u3e100º), extensors acted as flexors. The effective mechanical advantage (musculo-apodeme moment arm/leg moment arm = 0.10) resulted in the six femoral extensor muscles of the model developing a summed force (1.4N) equal to over 50 times the body weight. The model\u27s three major force-producing extensor muscles attained 95% of their maximum force, moment arm and moment at the joint angle used by the animal during wedging

Walking and Running in the Red-Legged Running Frog, Kassina Maculata

Although most frog species are specialized for jumping or swimming, Kassina maculata (red-legged running frog) primarily uses a third type of locomotion during which the hindlimbs alternate. In the present study, we examined Kassina\u27s distinct locomotory mode to determine whether these frogs walk or run and how their gait may change with speed. We used multiple methods to distinguish between terrestrial gaits: the existence or absence of an aerial phase, duty factor, relative footfall patterns and the mechanics of the animal\u27s center of mass (COM). To measure kinematic and kinetic variables, we recorded digital video as the animals moved over a miniature force platform (N=12 individuals). With respect to footfall patterns, the frogs used a single gait and walked at all speeds examined. Duty factor always exceeded 0.59. Based on COM mechanics, however, the frogs used both walking and running gaits. At slower speeds, the fluctuations in the horizontal kinetic energy (Ek) and gravitational potential energy (Ep) of the COM were largely out of phase, indicating a vaulting or walking gait. In most of the trials, Kassina used a combined gait at intermediate speeds, unlike cursorial animals with distinct gait transitions. This combined gait, much like a mammalian gallop, exhibited the mechanics of both vaulting and bouncing gaits. At faster speeds, the Ek and Ep of Kassina\u27s COM were more in phase, indicating the use of a bouncing or running gait. Depending on the definition used to distinguish between walking and running, Kassina either only used a walking gait at all speeds or used a walking gait at slower speeds but then switched to a running gait as speed increased

In Situ Muscle Power Differs Without Varying In Vitro Mechanical Properties in Two Insect Leg Muscles Innervated by the Same Motor Neuron

The mechanical behavior of muscle during locomotion is often predicted by its anatomy, kinematics, activation pattern and contractile properties. The neuromuscular design of the cockroach leg provides a model system to examine these assumptions, because a single motor neuron innervates two extensor muscles operating at a single joint. Comparisons of the in situ measurements under in vivo running conditions of muscle 178 to a previously examined muscle (179) demonstrate that the same inputs (e.g. neural signal and kinematics) can result in different mechanical outputs. The same neural signal and kinematics, as determined during running, can result in different mechanical functions, even when the two anatomically similar muscles possess the same contraction kinetics, force-velocity properties and tetanic force-length properties. Although active shortening greatly depressed force under in vivo-like strain and stimulation conditions, force depression was similarly proportional to strain, similarly inversely proportional to stimulation level, and similarly independent of initial length and shortening velocity between the two muscles. Lastly, passive pre-stretch enhanced force similarly between the two muscles. The forces generated by the two muscles when stimulated with their in vivo pattern at lengths equal to or shorter than rest length differed, however. Overall, differences between the two muscles in their submaximal force-length relationships can account for up to 75% of the difference between the two muscles in peak force generated at short lengths observed during oscillatory contractions. Despite the fact that these muscles act at the same joint, are stimulated by the same motor neuron with an identical pattern, and possess many of the same in vitro mechanical properties, the mechanical outputs of two leg extensor muscles can be vastly different

Moderate Dehydration Decreases Locomotor Performance of the Ghost Crab, Ocypode quadrata

The effect of dehydration on the aerobic metabolism and endurance of sustained, terrestrial locomotion was determined for the ghost crab, Ocypode quadrata, The rate of evaporative water loss, measured as the percentage of decrease in body mass per hour, was influenced by ambient temperature (Tₐ), Increasing Tₐ from 24° C to 30° C (40%-50% relative humidity) increased the rate of water loss from 2.3% h­­­­ˉ¹ ± 0.2% h­­­­ˉ¹ to 3.6% h­­­­ˉ¹ ± 0.6% h­­­­ˉ¹. Crabs were divided into three treatment groups to determine the effect of dehydration on aerobic metabolism: hydrated control crabs, slowly dehydrated crabs, and rapidly dehydrated crabs. Hydrated control crabs lost only 1.2% of their initial body mass. Slowly dehydrated crabs were dehydrated by 3.6% of their initial body mass at a rate of 2.3% hˉ¹. Finally, rapidly dehydrated crabs were dehydrated by 3.6% of their initial body mass at a rate of 3.6% hˉ¹. The maximal rate of oxygen consumption (Vo_2max) determined during treadmill exercise was decreased by 30% for slowly dehydrated crabs and by 70% for rapidly dehydrated crabs, as compared to hydrated controls. The minimum cost of locomotion was independent of the dehydration state for hydrated and slowly dehydrated crabs but was 62% lower for rapidly dehydrated crabs. Endurance was correlated with the speed at which Vo_2max was attained (the maximum aerobic speed [MAS]). The MAS was highest for hydrated control crabs and was decreased by 32% for slowly dehydrated crabs and by 68% for rapidly dehydrated crabs. We conclude that moderate dehydration can substantially decrease the ghost crab\u27s capacity for sustained, terrestrial locomotion

Energy Absorption During Running by Leg Muscles in a Cockroach

Biologists have traditionally focused on a muscle\u27s ability to generate power. By determining muscle length, strain and activation pattern in the cockroach Blaberus discoidalis, we discovered leg extensor muscles that operate as active dampers that only absorb energy during running. Data from running animals were compared with measurements of force and power production of isolated muscles studied over a range of stimulus conditions and muscle length changes. We studied the trochanter-femoral extensor muscles 137 and 179, homologous leg muscles of the mesothoracic and metathoracic legs, respectively. Because each of these muscles is innervated by a single excitatory motor axon, the activation pattern of the muscle could be defined precisely. Work loop studies using sinusoidal strains at 8 Hz showed these trochanter-femoral extensor muscles to be quite capable actuators, able to generate a maximum of 19-25 W kg-1 (at 25ºC). The optimal conditions for power output were four stimuli per cycle (interstimulus interval 11 ms), a strain of approximately 4%, and a stimulation phase such that the onset of the stimulus burst came approximately half-way through the lengthening phase of the cycle. High-speed video analysis indicated that the actual muscle strain during running was 12% in the mesothoracic muscles and 16% in the metathoracic ones. Myographic recordings during running showed on average 3-4 muscle action potentials per cycle, with the timing of the action potentials such that the burst usually began shortly after the onset of shortening. Imposing upon the muscle in vitro the strain, stimulus number and stimulus phase characteristic of running generated work loops in which energy was absorbed (-25 W kg-1) rather than produced. Simulations exploring a wide parameter space revealed that the dominant parameter that determines function during running is the magnitude of strain. Strains required for the maximum power output by the trochanter-femoral extensor muscles simply do not occur during constant, average-speed running. Joint angle ranges of the coxa-trochanter-femur joint during running were 3-4 times greater than the changes necessary to produce maximum power output. None of the simulated patterns of stimulation or phase resulted in power production when strain magnitude was greater than 5%. The trochanter-femoral extensor muscles 137/179 of a cockroach running at its preferred speed of 20 cm s-1 do not operate under conditions which maximize either power output or efficiency. In vitro measurements, however, demonstrate that these muscles absorb energy, probably to provide control of leg flexion and to aid in its reversal

Kinematic Evidence for Superfast Locomotory Muscle in Two Species of Teneriffiid Mites

Locomotory muscles typically operate over a narrow range of contraction frequencies, characterized by the predominant fiber types and functional roles. The highest documented frequencies in the synchronous sound-producing muscles of insects (550 Hz) and toadfish (200 Hz) far exceed the contraction frequencies observed in weight-bearing locomotory muscles, which have maximum documented frequencies below 15-30 Hz. Laws of scaling, however, predict that smaller arthropods may employ stride frequencies exceeding this range. In this study we measured running speed and stride frequency in two undescribed species of teneriffiid mites from the coastal sage scrub of southern California. Relative speeds of both species [129-133 body lengths (BL)s(-1)] are among the fastest documented for any animal. Measured stride frequencies for both species far exceed those documented for any weight-bearing locomotory muscle, with measured values for one species ranging from 93 Hz at 25 degrees C to 111 Hz at 45 degrees C. Stride frequencies either closely approximate or, for one species, exceed predicted values based on an interspecific scaling of frequency and animal mass. Consequently, while the ultra-high frequencies of these muscles must depend on appropriately scaled kinetics of the calcium transient and contraction-relaxation cycle, these do not appear to limit the operating frequencies during running. The predicted low muscle forces operating at these very high frequencies evidently suffice for locomotion, probably because of the larger relative muscle force generated by smaller animals

Beyond the standard seesaw: neutrino masses from Kahler operators and broken supersymmetry

We investigate supersymmetric scenarios in which neutrino masses are generated by effective d=6 operators in the Kahler potential, rather than by the standard d=5 superpotential operator. First, we discuss some general features of such effective operators, also including SUSY-breaking insertions, and compute the relevant renormalization group equations. Contributions to neutrino masses arise at low energy both at the tree level and through finite threshold corrections. In the second part we present simple explicit realizations in which those Kahler operators arise by integrating out heavy SU(2)_W triplets, as in the type II seesaw. Distinct scenarios emerge, depending on the mechanism and the scale of SUSY-breaking mediation. In particular, we propose an appealing and economical picture in which the heavy seesaw mediators are also messengers of SUSY breaking. In this case, strong correlations exist among neutrino parameters, sparticle and Higgs masses, as well as lepton flavour violating processes. Hence, this scenario can be tested at high-energy colliders, such as the LHC, and at lower energy experiments that measure neutrino parameters or search for rare lepton decays.Comment: LaTeX, 34 pages; some corrections in Section

JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition

Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617Fand mutant IDH1R132Hor Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617FIdh2R140Q–mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both JAK2mutand IDH2mutmutations. Taken together, these data suggest that combined JAK and IDH inhibition May offer a therapeutic advantage in this high-risk MPN subtype.Damon Runyon Cancer Research Foundation (DRG-2241-15)Howard Hughes Medical Institute (Faculty Scholars Award)Stand Up To CancerNational Cancer Institute (U.S.) (P50CA165962)National Cancer Institute (U.S.) (P30CA14051)Koch Institute for Integrative Cancer Research ( Dana-Farber Harvard Cancer Center Bridge Project)Leukemia & Lymphoma Society of America. Specialized Center of Research (SCOR) ProgramNational Institutes of Health (U.S.) (grant U54OD020355-01)National Institutes of Health (U.S.) (grant NCI R01CA172636)National Institutes of Health (U.S.) (grant R35CA197594)National Cancer Institute (U.S.) (Cancer Center Support Grant (P30 CA008747)