Differences in Abdominal Muscle Thickness, Strength, and Endurance in Persons Who Are Runners, Active, and Inactive.

BACKGROUND: Core musculature is important for efficiency during activities including running. Both abdominal muscle strength and endurance contribute to this efficiency. The purpose of this study is to determine what differences and relationships exist in abdominal muscle thickness, strength, and endurance among persons who are runners, active, and inactive. HYPOTHESIS: Persons in the running group would show significantly greater abdominal muscle thickness, muscle strength, and muscle endurance compared with those in the nonrunning groups. STUDY DESIGN: Quantitative cohort design. LEVEL OF EVIDENCE: Level 2b. METHODS: A total of 78 subjects aged 18 to 27 years were divided into 3 groups: runners, active, and inactive. Assessment included abdominal muscle thickness via diagnostic ultrasound (Mindray North America), strength using a static Isotrack dynamometer (JTech Medical), and abdominal muscle endurance using a side plank. Statistical analysis using analysis of variance, t tests, and Pearson's correlation coefficients and partial correlations was performed using SPSS Version 26 with a significance level of P < 0.05. RESULTS: Significantly greater muscle thickness of internal obliques (IOs) at rest and during contraction was found in the running group compared with the active group, the active group compared with the inactive group, and the running group compared with the inactive group. There were no statistically significant differences in overall strength measured by dynamometry among the 3 groups. Plank time was significantly greater for the running group compared with the other 2 groups. Male participants were greater in all areas: strength, plank time as a measure of muscle endurance, and muscle thickness. Body mass index was significantly correlated with resting thickness, muscle endurance, and muscle strength. CONCLUSION: Persons who run, are active, and are inactive use their abdominal muscles differently. Runners have thicker IOs and better abdominal muscle endurance than the other 2 groups. Focusing on endurance training of the obliques may be beneficial for persons who run. CLINICAL RELEVANCE: This research could contribute to developing core training programs to ensure runners target the correct abdominal muscles with the best type of training.

Discovery of Sulfonamide-Derived Agonists of SOS1-Mediated Nucleotide Exchange on RAS Using Fragment-Based Methods.

The nucleotide exchange factor Son of Sevenless (SOS) catalyzes the activation of RAS by converting it from its inactive GDP-bound state to its active GTP-bound state. Recently, we have reported the discovery of small-molecule allosteric activators of SOS1 that can increase the amount of RAS-GTP in cells. The compounds can inhibit ERK phosphorylation at higher concentrations by engaging a feedback mechanism. To further study this process, we sought different chemical matter from an NMR-based fragment screen using selective methyl labeling. To aid this process, several Ile methyl groups located in different binding sites of the protein were assigned and used to categorize the NMR hits into different classes. Hit to lead optimization using an iterative structure-based design paradigm resulted in compounds with improvements in binding affinity. These improved molecules of a different chemical class increase SOS1cat-mediated nucleotide exchange on RAS and display cellular action consistent with our prior results.

Goats decrease hindlimb stiffness when walking over compliant surfaces.

Leg stiffness, commonly estimated as the 'compression' of a defined leg element in response to a load, has long been used to characterize terrestrial locomotion. This study investigated how goats adjust the stiffness of their hindlimbs to accommodate surfaces of different stiffness. Goats provide a compelling animal model for studying leg stiffness modulation, because they skillfully ambulate over a range of substrates that vary in compliance. To investigate the adjustments that goats make when walking over such substrates, ground reaction forces and three-dimensional trajectories of hindlimb markers were recorded as goats walked on rigid, rubber and foam surfaces. Net joint moments, power and work at the hip, knee, ankle and metatarsophalangeal joints were estimated throughout stance via inverse dynamics. Hindlimb stiffness was estimated from plots of total leg force versus total leg length, and individual joint stiffness was estimated from plots of joint moment versus joint angle. Our results support the hypothesis that goats modulate hindlimb stiffness in response to surface stiffness; specifically, hindlimb stiffness decreased on the more compliant surfaces (P<0.002). Estimates of joint stiffness identified hip and ankle muscles as the primary drivers of these adjustments. When humans run on compliant surfaces, they generally increase leg stiffness to preserve their center-of-mass mechanics. We did not estimate center-of-mass mechanics in this study; nevertheless, our estimates of hindlimb stiffness suggest that goats exhibit a different behavior. This study offers new insight into mechanisms that allow quadrupeds to modulate their gait mechanics when walking on surfaces of variable compliance.

Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer.

Overexpression of myeloid cell leukemia-1 (Mcl-1) in cancers correlates with high tumor grade and poor survival. Additionally, Mcl-1 drives intrinsic and acquired resistance to many cancer therapeutics, including B cell lymphoma 2 family inhibitors, proteasome inhibitors, and antitubulins. Therefore, Mcl-1 inhibition could serve as a strategy to target cancers that require Mcl-1 to evade apoptosis. Herein, we describe the use of structure-based design to discover a novel compound (42) that robustly and specifically inhibits Mcl-1 in cell culture and animal xenograft models. Compound 42 binds to Mcl-1 with picomolar affinity and inhibited growth of Mcl-1-dependent tumor cell lines in the nanomolar range. Compound 42 also inhibited the growth of hematological and triple negative breast cancer xenografts at well-tolerated doses. These findings highlight the use of structure-based design to identify small molecule Mcl-1 inhibitors and support the use of 42 as a potential treatment strategy to block Mcl-1 activity and induce apoptosis in Mcl-1-dependent cancers.

Small Molecule SOS1 Agonists Modulate MAPK and PI3K Signaling via Independent Cellular Responses.

Activating mutations in RAS can lead to oncogenesis by enhancing downstream signaling, such as through the MAPK and PI3K pathways. Therefore, therapeutically targeting RAS may perturb multiple signaling pathways simultaneously. One method for modulating RAS signaling is to target the activity of the guanine nucleotide exchange factor SOS1. Our laboratory has discovered compounds that bind to SOS1 and activate RAS. Interestingly, these SOS1 agonist compounds elicit biphasic modulation of ERK phosphorylation and simultaneous inhibition of AKT phosphorylation levels. Here, we utilized multiple chemically distinct compounds to elucidate whether these effects on MAPK and PI3K signaling by SOS1 agonists were mechanistically linked. In addition, we used CRISPR/Cas9 gene-editing to generate clonally derived SOS1 knockout cells and identified a potent SOS1 agonist that rapidly elicited on-target molecular effects at substantially lower concentrations than those causing off-target effects. Our findings will allow us to further define the on-target utility of SOS1 agonists.

Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS.

Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical cellular processes. Aberrant RAS activity is involved in ∼30% of all human cancers; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation. Here, we describe a new series of benzimidazole-derived SOS1 agonists. Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at submicromolar concentrations, bind to SOS1 with low double-digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. These compounds represent the most potent series of SOS1 agonists reported to date.

Understanding the Species Selectivity of Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors.

To test for on target toxicity of a new chemical entity, it is important to have comparable binding affinities of the compound in the target proteins from humans and the test species. To evaluate our myeloid cell leukemia-1 (Mcl-1) inhibitors, we tested them against rodent Mcl-1 and found a significant loss of binding affinity when compared to that seen with human Mcl-1. To understand the affinity loss, we used sequence alignments and structures of human Mcl-1/inhibitor complexes to identify the important differences in the amino acid sequences. One difference is human L246 (F226 in rat, F227 in mouse) in the ligand binding pocket. Mutating rat F226 to a Leu restores affinity, but the mouse F227L mutant still has a ligand affinity that is lower than that of human Mcl-1. Another mutation of mouse F267, located ∼12 Šfrom the ligand pocket, to the human/rat cysteine, F267C, improved the affinity and combined with F227L resulted in a mutant mouse protein with a binding affinity similar to that of human Mcl-1. To help understand the structural components of the affinity loss, we obtained an X-ray structure of a mouse Mcl-1/inhibitor complex and identified how the residue changes reduced compound complementarity. Finally, we tested Mcl-1 of other preclinical animal models (canine, monkey, rabbit, and ferret) that are identical to humans in terms of these two residues and found that their Mcl-1 bound our compounds with affinities comparable to that of human Mcl-1. These results have implications for understanding ligand selectivity for similar proteins and for the interpretation of preclinical toxicology studies with Mcl-1 inhibitors.

Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design.

Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here, we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1-sensitive cells. Thus, they represent useful compounds to study the implication of Mcl-1 inhibition in cancer and serve as potentially useful starting points toward the discovery of anti-Mcl-1 therapeutics.

Does a two-element muscle model offer advantages when estimating ankle plantar flexor forces during human cycling?

Traditional Hill-type muscle models, parameterized using high-quality experimental data, are often "too weak" to reproduce the joint torques generated by healthy adults during rapid, high force tasks. This study investigated whether the failure of these models to account for different types of motor units contributes to this apparent weakness; if so, muscle-driven simulations may rely on excessively high muscle excitations to generate a given force. We ran a series of forward simulations that reproduced measured ankle mechanics during cycling at five cadences ranging from 60 to 140 RPM. We generated both "nominal" simulations, in which an abstract ankle model was actuated by a 1-element Hill-type plantar flexor with a single contractile element (CE), and "test" simulations, in which the same model was actuated by a 2-element plantar flexor with two CEs that accounted for the force-generating properties of slower and faster motor units. We varied the total excitation applied to the 2-element plantar flexor between 60 and 105% of the excitation from each nominal simulation, and we varied the amount distributed to each CE between 0 and 100% of the total. Within this test space, we identified the excitation level and distribution, at each cadence, that best reproduced the plantar flexor forces generated in the nominal simulations. Our comparisons revealed that the 2-element model required substantially less total excitation than the 1-element model to generate comparable forces, especially at higher cadences. For instance, at 140 RPM, the required excitation was reduced by 23%. These results suggest that a 2-element model, in which contractile properties are "tuned" to represent slower and faster motor units, can increase the apparent strength and perhaps improve the fidelity of simulations of tasks with varying mechanical demands.

Why are Antagonist Muscles Co-activated in My Simulation? A Musculoskeletal Model for Analysing Human Locomotor Tasks.

Existing "off-the-shelf" musculoskeletal models are problematic when simulating movements that involve substantial hip and knee flexion, such as the upstroke of pedalling, because they tend to generate excessive passive fibre force. The goal of this study was to develop a refined musculoskeletal model capable of simulating pedalling and fast running, in addition to walking, which predicts the activation patterns of muscles better than existing models. Specifically, we tested whether the anomalous co-activation of antagonist muscles, commonly observed in simulations, could be resolved if the passive forces generated by the underlying model were diminished. We refined the OpenSim™ model published by Rajagopal et al. (IEEE Trans Biomed Eng 63:1-1, 2016) by increasing the model's range of knee flexion, updating the paths of the knee muscles, and modifying the force-generating properties of eleven muscles. Simulations of pedalling, running and walking based on this model reproduced measured EMG activity better than simulations based on the existing model-even when both models tracked the same subject-specific kinematics. Improvements in the predicted activations were associated with decreases in the net passive moments; for example, the net passive knee moment during the upstroke of pedalling decreased from 36.9 N m (existing model) to 6.3 N m (refined model), resulting in a dramatic decrease in the co-activation of knee flexors. The refined model is available from SimTK.org and is suitable for analysing movements with up to 120° of hip flexion and 140° of knee flexion.

Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors.

Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that when overexpressed is associated with high tumor grade, poor survival, and resistance to chemotherapy. Mcl-1 is amplified in many human cancers, and knockdown of Mcl-1 using RNAi can lead to apoptosis. Thus, Mcl-1 is a promising cancer target. Here, we describe the discovery of picomolar Mcl-1 inhibitors that cause caspase activation, mitochondrial depolarization, and selective growth inhibition. These compounds represent valuable tools to study the role of Mcl-1 in cancer and serve as useful starting points for the discovery of clinically useful Mcl-1 inhibitors. PDB ID CODES: Comp. 2: 5IEZ; Comp. 5: 5IF4.

Quantifying Achilles tendon force in vivo from ultrasound images.

This study evaluated a procedure for estimating in vivo Achilles tendon (AT) force from ultrasound images. Two aspects of the procedure were tested: (i) accounting for subject-specific AT stiffness and (ii) accounting for changes in the relative electromyographic (EMG) intensities of the three triceps surae muscles. Ten cyclists pedaled at 80rpm while a comprehensive set of kinematic, kinetic, EMG, and ultrasound data were collected. Subjects were tested at four crank loads, ranging from 14 to 44Nm (115 to 370W). AT forces during cycling were estimated from AT length changes and from AT stiffness, which we derived for each subject from ultrasound data and from plantar flexion torques measured during isometric tests. AT length changes were measured by tracking the muscle-tendon junction of the medial gastrocnemius (MG) relative to its insertion on the calcaneus. Because the relative EMG intensities of the triceps surae muscles varied with load during cycling, we divided subjects׳ measured AT length changes by a scale factor, defined as the square root of the relative EMG intensity of the MG, weighted by the fractional physiological cross-sectional areas of the three muscles, to estimate force. Subjects׳ estimated AT forces during cycling increased with load (p<0.05). On average, peak forces ranged from 920±96N (14Nm, 115W) to 1510±129N (44Nm, 370W). For most subjects, ankle moments derived from the ultrasound-based AT strains were 5-12% less than the net ankle moments calculated from inverse dynamics (r2=0.71±0.28, RMSE=8.1±0.33Nm). Differences in the moments increased substantially when we did not account for changes in the muscles׳ relative EMG intensities with load or, in some subjects, when we used an average stiffness, rather than a subject-specific value. The proposed methods offer a non-invasive approach for studying in vivo muscle-tendon mechanics.

Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods.

Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family of proteins responsible for the regulation of programmed cell death. Amplification of Mcl-1 is a common genetic aberration in human cancer whose overexpression contributes to the evasion of apoptosis and is one of the major resistance mechanisms for many chemotherapies. Mcl-1 mediates its effects primarily through interactions with pro-apoptotic BH3 containing proteins that achieve high affinity for the target by utilizing four hydrophobic pockets in its binding groove. Here we describe the discovery of Mcl-1 inhibitors using fragment-based methods and structure-based design. These novel inhibitors exhibit low nanomolar binding affinities to Mcl-1 and >500-fold selectivity over Bcl-xL. X-ray structures of lead Mcl-1 inhibitors when complexed to Mcl-1 provided detailed information on how these small-molecules bind to the target and were used extensively to guide compound optimization.

The capacity of the human iliotibial band to store elastic energy during running.

The human iliotibial band (ITB) is a poorly understood fascial structure that may contribute to energy savings during locomotion. This study evaluated the capacity of the ITB to store and release elastic energy during running, at speeds ranging from 2-5m/s, using a model that characterizes the three-dimensional musculoskeletal geometry of the human lower limb and the force-length properties of the ITB, tensor fascia lata (TFL), and gluteus maximus (GMax). The model was based on detailed analyses of muscle architecture, dissections of 3-D anatomy, and measurements of the muscles' moment arms about the hip and knee in five cadaveric specimens. The model was used, in combination with measured joint kinematics and published EMG recordings, to estimate the forces and corresponding strains in the ITB during running. We found that forces generated by TFL and GMax during running stretch the ITB substantially, resulting in energy storage. Anterior and posterior regions of the ITB muscle-tendon units (MTUs) show distinct length change patterns, in part due to different moment arms at the hip and knee. The posterior ITB MTU likely stores more energy than the anterior ITB MTU because it transmits larger muscle forces. We estimate that the ITB stores about 1J of energy per stride during slow running and 7J during fast running, which represents approximately 14% of the energy stored in the Achilles tendon at a comparable speed. This previously unrecognized mechanism for storing elastic energy may be an adaptation to increase human locomotor economy.

The human iliotibial band is specialized for elastic energy storage compared with the chimp fascia lata.

This study examines whether the human iliotibial band (ITB) is specialized for elastic energy storage relative to the chimpanzee fascia lata (FL). To quantify the energy storage potential of these structures, we created computer models of human and chimpanzee lower limbs based on detailed anatomical dissections. We characterized the geometry and force-length properties of the FL, tensor fascia lata (TFL) and gluteus maximus (GMax) in four chimpanzee cadavers based on measurements of muscle architecture and moment arms about the hip and knee. We used the chimp model to estimate the forces and corresponding strains in the chimp FL during bipedal walking, and compared these data with analogous estimates from a model of the human ITB, accounting for differences in body mass and lower extremity posture. We estimate that the human ITB stores 15- to 20-times more elastic energy per unit body mass and stride than the chimp FL during bipedal walking. Because chimps walk with persistent hip flexion, the TFL and portions of GMax that insert on the FL undergo smaller excursions (origin to insertion) than muscles that insert on the human ITB. Also, because a smaller fraction of GMax inserts on the chimp FL than on the human ITB, and thus its mass-normalized physiological cross-sectional area is about three times less in chimps, the chimp FL probably transmits smaller muscle forces. These data provide new evidence that the human ITB is anatomically derived compared with the chimp FL and potentially contributes to locomotor economy during bipedal locomotion.

Validation of Hill-type muscle models in relation to neuromuscular recruitment and force-velocity properties: predicting patterns of in vivo muscle force.

We review here the use and reliability of Hill-type muscle models to predict muscle performance under varying conditions, ranging from in situ production of isometric force to in vivo dynamics of muscle length change and force in response to activation. Muscle models are frequently used in musculoskeletal simulations of movement, particularly when applied to studies of human motor performance in which surgically implanted transducers have limited use. Musculoskeletal simulations of different animal species also are being developed to evaluate comparative and evolutionary aspects of locomotor performance. However, such models are rarely validated against direct measures of fascicle strain or recordings of muscle-tendon force. Historically, Hill-type models simplify properties of whole muscle by scaling salient properties of single fibers to whole muscles, typically accounting for a muscle's architecture and series elasticity. Activation of the model's single contractile element (assigned the properties of homogenous fibers) is also simplified and is often based on temporal features of myoelectric (EMG) activation recorded from the muscle. Comparison of standard one-element models with a novel two-element model and with in situ and in vivo measures of EMG, fascicle strain, and force recorded from the gastrocnemius muscles of goats shows that a two-element Hill-type model, which allows independent recruitment of slow and fast units, better predicts temporal patterns of in situ and in vivo force. Recruitment patterns of slow/fast units based on wavelet decomposition of EMG activity in frequency-time space are generally correlated with the intensity spectra of the EMG signals, the strain rates of the fascicles, and the muscle-tendon forces measured in vivo, with faster units linked to greater strain rates and to more rapid forces. Using direct measures of muscle performance to further test Hill-type models, whether traditional or more complex, remains critical for establishing their accuracy and essential for verifying their applicability to scientific and clinical studies of musculoskeletal function.

Accuracy of gastrocnemius muscles forces in walking and running goats predicted by one-element and two-element Hill-type models.

Hill-type models are commonly used to estimate muscle forces during human and animal movement-yet the accuracy of the forces estimated during walking, running, and other tasks remains largely unknown. Further, most Hill-type models assume a single contractile element, despite evidence that faster and slower motor units, which have different activation-deactivation dynamics, may be independently or collectively excited. This study evaluated a novel, two-element Hill-type model with "differential" activation of fast and slow contractile elements. Model performance was assessed using a comprehensive data set (including measures of EMG intensity, fascicle length, and tendon force) collected from the gastrocnemius muscles of goats during locomotor experiments. Muscle forces predicted by the new two-element model were compared to the forces estimated using traditional one-element models and to the forces measured in vivo using tendon buckle transducers. Overall, the two-element model resulted in the best predictions of in vivo gastrocnemius force. The coefficient of determination, r(2), was up to 26.9% higher and the root mean square error, RMSE, was up to 37.4% lower for the two-element model than for the one-element models tested. All models captured salient features of the measured muscle force during walking, trotting, and galloping (r(2)=0.26-0.51), and all exhibited some errors (RMSE=9.63-32.2% of the maximum in vivo force). These comparisons provide important insight into the accuracy of Hill-type models. The results also show that incorporation of fast and slow contractile elements within muscle models can improve estimates of time-varying, whole muscle force during locomotor tasks.

Modulation of joint moments and work in the goat hindlimb with locomotor speed and surface grade.

Goats and other quadrupeds must modulate the work output of their muscles to accommodate the changing mechanical demands associated with locomotion in their natural environments. This study examined which hindlimb joint moments goats use to generate and absorb mechanical energy on level and sloped surfaces over a range of locomotor speeds. Ground reaction forces and the three-dimensional locations of joint markers were recorded as goats walked, trotted and galloped over 0, +15 and -15 deg sloped surfaces. Net joint moments, powers and work were estimated at the goats' hip, knee, ankle and metatarsophalangeal joints throughout the stance phase via inverse dynamics calculations. Differences in locomotor speed on the level, inclined and declined surfaces were characterized and accounted for by fitting regression equations to the joint moment, power and work data plotted versus non-dimensionalized speed. During level locomotion, the net work generated by moments at each of the hindlimb joints was small (less than 0.1 J kg(-1) body mass) and did not vary substantially with gait or locomotor speed. During uphill running, by contrast, mechanical energy was generated at the hip, knee and ankle, and the net work at each of these joints increased dramatically with speed (P<0.05). The greatest increases in positive joint work occurred at the hip and ankle. During downhill running, mechanical energy was decreased in two main ways: goats generated larger knee extension moments in the first half of stance, absorbing energy as the knee flexed, and goats generated smaller ankle extension moments in the second half of stance, delivering less energy. The goats' hip extension moment in mid-stance was also diminished, contributing to the decrease in energy. These analyses offer new insight into quadrupedal locomotion, clarifying how the moments generated by hindlimb muscles modulate mechanical energy at different locomotor speeds and grades, as needed to accommodate the demands of variable terrain.

Recruitment of faster motor units is associated with greater rates of fascicle strain and rapid changes in muscle force during locomotion.

Animals modulate the power output needed for different locomotor tasks by changing muscle forces and fascicle strain rates. To generate the necessary forces, appropriate motor units must be recruited. Faster motor units have faster activation-deactivation rates than slower motor units, and they contract at higher strain rates; therefore, recruitment of faster motor units may be advantageous for tasks that involve rapid movements or high rates of work. This study identified motor unit recruitment patterns in the gastrocnemii muscles of goats and examined whether faster motor units are recruited when locomotor speed is increased. The study also examined whether locomotor tasks that elicit faster (or slower) motor units are associated with increased (or decreased) in vivo tendon forces, force rise and relaxation rates, fascicle strains and/or strain rates. Electromyography (EMG), sonomicrometry and muscle-tendon force data were collected from the lateral and medial gastrocnemius muscles of goats during level walking, trotting and galloping and during inclined walking and trotting. EMG signals were analyzed using wavelet and principal component analyses to quantify changes in the EMG frequency spectra across the different locomotor conditions. Fascicle strain and strain rate were calculated from the sonomicrometric data, and force rise and relaxation rates were determined from the tendon force data. The results of this study showed that faster motor units were recruited as goats increased their locomotor speeds from level walking to galloping. Slow inclined walking elicited EMG intensities similar to those of fast level galloping but different EMG frequency spectra, indicating that recruitment of the different motor unit types depended, in part, on characteristics of the task. For the locomotor tasks and muscles analyzed here, recruitment patterns were generally associated with in vivo fascicle strain rates, EMG intensity and tendon force. Together, these data provide new evidence that changes in motor unit recruitment have an underlying mechanical basis, at least for certain locomotor tasks.

A muscle's force depends on the recruitment patterns of its fibers.

Biomechanical models of whole muscles commonly used in simulations of musculoskeletal function and movement typically assume that the muscle generates force as a scaled-up muscle fiber. However, muscles are comprised of motor units that have different intrinsic properties and that can be activated at different times. This study tested whether a muscle model comprised of motor units that could be independently activated resulted in more accurate predictions of force than traditional Hill-type models. Forces predicted by the models were evaluated by direct comparison with the muscle forces measured in situ from the gastrocnemii in goats. The muscle was stimulated tetanically at a range of frequencies, muscle fiber strains were measured using sonomicrometry, and the activation patterns of the different types of motor unit were calculated from electromyographic recordings. Activation patterns were input into five different muscle models. Four models were traditional Hill-type models with different intrinsic speeds and fiber-type properties. The fifth model incorporated differential groups of fast and slow motor units. For all goats, muscles and stimulation frequencies the differential model resulted in the best predictions of muscle force. The in situ muscle output was shown to depend on the recruitment of different motor units within the muscle.