Anatomical predictors of maximum isometric and concentric knee extensor moment.

The most important anatomical determinants of in vivo joint moment magnitude have yet to be defined. Relationships between maximal knee extensor moment and quadriceps muscle volume, anatomical (ACSA) and physiological (PCSA) cross-sectional area, muscle architecture and moment arm (MA) were compared. Nineteen untrained men and women performed maximal isokinetic knee extensions under isometric conditions (90 degrees joint angle) and at 30 degrees and 300 degrees s(-1). Magnetic resonance and ultrasound imaging techniques were used to measure vastus lateralis PCSA and fascicle length (FL), quadriceps ACSA, volume and patellar tendon MA. Muscle volume was the best predictor of extensor moment measured isometrically (R(2) = 0.60) and at 30 degrees s(-1)(R (2) = 0.74). PCSA x FL was the best predictor of moment at 300 degrees s(-1) (R(2) = 0.59). MA was not an important predictor. ACSA was the second best predictor at all three speeds and could be recommended as an ideal measure given its relative ease of measurement.

Influence of concentric and eccentric resistance training on architectural adaptation in human quadriceps muscles.

Studies using animal models have been unable to determine the mechanical stimuli that most influence muscle architectural adaptation. We examined the influence of contraction mode on muscle architectural change in humans, while also describing the time course of its adaptation through training and detraining. Twenty-one men and women performed slow-speed (30 degrees /s) concentric-only (Con) or eccentric-only (Ecc) isokinetic knee extensor training for 10 wk before completing a 3-mo detraining period. Fascicle length of the vastus lateralis (VL), measured by ultrasonography, increased similarly in both groups after 5 wk (Delta(Con) = +6.3 +/- 3.0%, Delta(Ecc) = +3.1 +/- 1.6%, mean = +4.7 +/- 1.7%; P < 0.05). No further increase was found at 10 wk, although a small increase (mean approximately 2.5%; not significant) was evident after detraining. Fascicle angle increased in both groups at 5 wk (Delta(Con) = +11.1 +/- 4.0%, Delta(Ecc) = +11.9 +/- 5.4%, mean = 11.5 +/- 3.2%; P < 0.05) and 10 wk (Delta(Con) = +13.3 +/- 3.0%, Delta(Ecc) = +21.4 +/- 6.9%, mean = 17.9 +/- 3.7%; P < 0.01) in VL only and remained above baseline after detraining (mean = 13.2%); smaller changes in vastus medialis did not reach significance. The similar increase in fascicle length observed between the training groups mitigates against contraction mode being the predominant stimulus. Our data are also strongly indicative of 1) a close association between VL fascicle length and shifts in the torque-angle relationship through training and detraining and 2) changes in fascicle angle being driven by space constraints in the hypertrophying muscle. Thus muscle architectural adaptations occur rapidly in response to resistance training but are strongly influenced by factors other than contraction mode.

Investigation of the binding determinants of phosphopeptides targeted to the SRC homology 2 domain of the signal transducer and activator of transcription 3. Development of a high-affinity peptide inhibitor.

Signal transducer and activator of transcription 3 (Stat3) is a cytosolic transcription factor that relates signals from the cell membrane directly to the nucleus where it, in complex with other proteins, initiates the transcription of antiapoptotic and cell cycling genes, e.g., Bcl-x(L) and cyclin D1. In normal cells Stat3 transduces signals from cytokines such as IL-6 and growth factors such as the epidermal growth factor. Stat3 is constitutively activated in a number of human tumors. Antisense and dominant negative gene delivery result in apoptosis and reduced cell growth, thus this protein is an attractive target for anticancer drug design. As part of our research on the design of Src homology 2 (SH2) directed peptidomimetic inhibitors of Stat3, in this paper we describe structure-activity relationship studies that provide information on the nature of peptide-protein interactions of a high-affinity phosphopeptide inhibitor of Stat3 dimerization and DNA binding, Ac-Tyr(PO3H2)-Leu-Pro-Gln-Thr-Val-NH2, peptide 1. There is a hydrophobic surface on the SH2 domain that can accommodate lipophilic groups on the N-terminus. Of the amino acids tested, leucine provided the highest affinity at pY+1 and its main chain NH is involved with a hydrogen bond with Stat3, presumably Ser636. cis-3,4-Methanoproline is optimal as a backbone constraint at pY+2. The side chain amide protons of Gln are required for high-affinity interactions. The C-terminal dipeptide, Thr-Val, can be replaced with groups ranging in size from methyl to benzyl. We synthesized a phosphopeptide incorporating groups that provided increases in affinity at each position. Thus, hydrocinnamoyl-Tyr(PO3H2)-Leu-cis-3,4-methanoPro-Gln-NHBn, 50, was the highest affinity peptide, exhibiting an IC50 of 125 nM versus 290 nM for peptide 1 in a fluorescence polarization assay.

Leg stiffness in human running: Comparison of estimates derived from previously published models to direct kinematic-kinetic measures.

It is not presently clear whether mathematical models used to estimate leg stiffness during human running are valid. Therefore, leg stiffness during the braking phase of ground contact of running was calculated directly using synchronous kinematic (high-speed motion analysis) and kinetic (force platform) analysis, and compared to stiffness calculated using four previously published kinetic models. Nineteen well-trained male middle distance runners (age=21.1±4.1yr; VO(2max)=69.5±7.5mlO(2)kg(-1)min(-1)) completed a series of runs of increasing speed from 2.5 to 6.5ms(-1). Leg stiffness was calculated directly from kinetic-kinematic analysis using both vertical and horizontal forces to obtain the resultant force in the line of leg compression (Model 1). Values were also estimated using four previously published mathematical models where only force platform derived and anthropometric measures were required (Models 2-5; Morin et al., 2005, Morin et al., 2011, Blum et al., 2009, Farley et al., 1993, respectively). The greatest statistical similarity between leg stiffness values occurred with Models 1 and 2. The poorest similarity occurred when values from Model 4 were compared with Model 1. Analyses suggest that the poor correlation between Model 1 other models may have resulted from errors in the estimation in change in leg length during the braking phase. Previously published mathematical models did not provide accurate leg stiffness estimates, although Model 2, used by Morin et al. (2005), provided reasonable estimates that could be further improved by the removal of systematic error using a correction factor (K=1.0496K(Model2)).

Lack of effect of moderate-duration static stretching on plantar flexor force production and series compliance.

BACKGROUND: The effects of an acute bout of moderate-duration static stretching on plantar flexor force production, series compliance of the muscle-tendon unit, and levels of neuromuscular activation were examined. METHODS: Eighteen active individuals (9 men and 9 women) performed four 45-s static plantar flexor stretches and a time-matched control of no stretch (where subjects remained seated in the dynamometer for 4 min with no stretch being performed). Measures of peak isometric moment, rate of force development, neuromuscular activation (interpolated twitch technique and electromyography), twitch force characteristics, passive moment during stretch, and tendon elongation during maximal voluntary contractions were taken before and after the stretching. FINDINGS: Despite a significant stress-relaxation response during stretch (9.3%, P<0.01) there were no significant differences in peak isometric moment (P=0.35; effect size 0.13), rate of force development (P=0.93; effect size 0.01), neuromuscular activation (interpolated twitch: P=0.86; electromyography: P=0.09; effect size 0.02), or tendon elongation (P=0.61; effect size 0.07) after stretching. Twitch characteristics were also unchanged after stretching, although there was a reduction in the rate of twitch torque relaxation (RR(t); P<0.01). INTERPRETATION: The acute bout of moderate-duration static stretching did not impair the force generating capacity of the plantar flexors or negatively affect muscle-tendon mechanical properties. Static stretching may not always have detrimental consequences for force production. Thus, clinicians may be able to apply moderate-duration stretches to patients without risk of reducing muscular performance.

Changes in muscle force-length properties affect the early rise of force in vivo.

Changes in contractile rate of force development (RFD), measured within a short time interval from contraction initiation, were measured after a period of strength training that led to increases in muscle fascicle length but no measurable change in neuromuscular activity. The relationship between training-induced shifts in the moment-angle relation and changes in RFD measured to 30 ms (i.e., early) and 200 ms (i.e., late) from the onset of isometric knee extension force were examined; shifts in the moment-angle relation were used as an overall measure of changes in quadriceps muscle fascicle length. A significant proportion of the variance in RFD measured only in the initial contraction phase (0-30 ms) could be explained by shifts in the moment-angle relation (r=-0.66-0.71; R2=0.44-0.50). Training-induced increases in muscle fascicle length may lead to a reduced or complete lack of adaptive gains in contractile RFD, especially in the early contraction phase.

Conformationally constrained peptidomimetic inhibitors of signal transducer and activator of transcription. 3: Evaluation and molecular modeling.

Signal transducer and activator of transcription 3 (Stat3) is involved in aberrant growth and survival signals in malignant tumor cells and is a validated target for anticancer drug design. We are targeting its SH2 domain to prevent docking to cytokine and growth factor receptors and subsequent signaling. The amino acids of our lead phosphopeptide, Ac-pTyr-Leu-Pro-Gln-Thr-Val-NH(2), were replaced with conformationally constrained mimics. Structure-affinity studies led to the peptidomimetic, pCinn-Haic-Gln-NHBn (21), which had an IC(50) of 162 nM (fluorescence polarization), compared to 290 nM for the lead phosphopeptide (pCinn = 4-phosphoryloxycinnamate, Haic = (2S,5S)-5-amino-1,2,4,5,6,7-hexahydro-4-oxo-azepino[3,2,1-hi]indole-2-carboxylic acid). pCinn-Haic-Gln-OH was docked to the SH2 domain (AUTODOCK), and the two highest populated clusters were subjected to molecular dynamics simulations. Both converged to a common peptide conformation. The complex exhibits unique hydrogen bonding between Haic and Gln and Stat3 as well as hydrophobic interactions between the protein and pCinn and Haic.

Effect of contraction mode of slow-speed resistance training on the maximum rate of force development in the human quadriceps.

This study examined the effects of slow-speed resistance training involving concentric (CON, n = 10) versus eccentric (ECC, n = 11) single-joint muscle contractions on contractile rate of force development (RFD) and neuromuscular activity (EMG), and its maintenance through detraining. Isokinetic knee extension training was performed 3 x week(-1) for 10 weeks. Maximal isometric strength (+11.2%) and RFD (measured from 0-30/50/100/200 ms, respectively; +10.5%-20.5%) increased after 10 weeks (P < 0.01-0.05); however, there was no effect of training mode. Peak EMG amplitude and rate of EMG rise were not significantly altered with training or detraining. Subjects with below-median normalized RFD (RFD/MVC) at 0 weeks significantly increased RFD after 5- and 10-weeks training, which was associated with increased neuromuscular activity. Subjects who maintained their higher RFD after detraining also exhibited higher activity at detraining. Thus, only subjects with a lesser ability to rapidly attain their maximum force before training improved RFD with slow-speed resistance exercise.