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.

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.

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.

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.