Accreting protoplanets in the LkCa 15 transition disk.

Exoplanet detections have revolutionized astronomy, offering new insights into solar system architecture and planet demographics. While nearly 1,900 exoplanets have now been discovered and confirmed, none are still in the process of formation. Transition disks, protoplanetary disks with inner clearings best explained by the influence of accreting planets, are natural laboratories for the study of planet formation. Some transition disks show evidence for the presence of young planets in the form of disk asymmetries or infrared sources detected within their clearings, as in the case of LkCa 15 (refs 8, 9). Attempts to observe directly signatures of accretion onto protoplanets have hitherto proven unsuccessful. Here we report adaptive optics observations of LkCa 15 that probe within the disk clearing. With accurate source positions over multiple epochs spanning 2009-2015, we infer the presence of multiple companions on Keplerian orbits. We directly detect Hα emission from the innermost companion, LkCa 15 b, evincing hot (about 10,000 kelvin) gas falling deep into the potential well of an accreting protoplanet.

Is curvature of the force-velocity relationship affected by oxygen availability? Evidence from studies in ex vivo and in situ rat muscles.

The power of shortening contractions in skeletal muscle is determined by the force-velocity relationship. Fatigue has been reported to either increase or decrease the force-velocity curvature depending on experimental circumstances. These discrepant findings may be related to experimental differences in oxygen availability. We therefore investigated how the curvature of the force-velocity relationship in soleus and gastrocnemius rat muscles is affected during fatigue, in both an ex vivo setup without an intact blood perfusion and in an in situ setup with an intact blood perfusion. Furthermore, we investigated the effect of reduced oxygen concentrations and reduced diffusion distance on the curvature of the force-velocity relationship in ex vivo muscles, where muscle oxygen uptake relies on diffusion from the incubation medium. Muscles were electrically stimulated to perform repeated shortening contractions and force-velocity curves were determined in rested and fatigued conditions. The curvature increased during fatigue in the soleus muscles (both in situ and ex vivo), and decreased for the gastrocnemius muscles (in situ) or remained unchanged (ex vivo). Furthermore, under ex vivo conditions, neither reduced oxygen concentrations nor reduced diffusion distance conferred any substantial effect on the force-velocity curvature. In contrast, reduced oxygen availability and increased diffusion distance did increase the loss of maximal power during fatigue, mainly due to additional decreases in isometric force. We conclude that oxygen availability does not influence the fatigue-induced changes in force-velocity curvature. Rather, the observed variable fatigue profiles with regard to changes in curvature seem to be linked to the muscle fiber-type composition.

Blood lactate accumulation decreases during the slow component of oxygen uptake without a decrease in muscular efficiency.

Pulmonary oxygen uptake ([Formula: see text]) slowly increases during exercise above the anaerobic threshold, and this increase is called the slow component of [Formula: see text]. The mechanism of the increase in [Formula: see text] is assumed to be due to increasing energy cost associated with increasingly inefficient muscle contraction. We hypothesized that the increase in [Formula: see text] would be accompanied by a constant or increasing rate of accumulation of blood lactate, indicating sustained anaerobic metabolism while [Formula: see text] increased. Ten male subjects performed cycle ergometry for 3, 6, and 9 min at a power output representing 60% of the difference between lactate threshold and maximal [Formula: see text] while [Formula: see text] and blood lactate accumulation were measured. Blood lactate accumulation decreased over time, providing the energy equivalent of (mean ± SD) 1586 ± 265, 855 ± 287, and 431 ± 392 ml of [Formula: see text] during 0-3, 3-6, and 6-9 min of exercise, respectively. As duration progressed, [Formula: see text] supplied 86.3 ± 2.0, 93.6 ± 1.9, and 96.8 ± 2.9% of total energy from 0 to 3, 3 to 6, and 6 to 9 min, respectively, while anaerobic contribution decreased. There was no change in total energy cost after 3 min, except that required by ventilatory muscles for the progressive increase in ventilation. The slow component of [Formula: see text] is accompanied by decreasing anaerobic energy contribution beyond 3 min during heavy exercise.

Cerebral small vessel disease in aging and Alzheimer's disease: a comparative study using MRI and SPECT.

BACKGROUND: White matter hyperintensities (WMH) are associated with aging and are prevalent in various brain pathologies. The purpose of the current study was to characterize WMH perfusion in age-matched elderly controls (ECs) and patients with Alzheimer's disease (ADs). METHODS: Fifty ECs (23 men) and 61 ADs (33 men) underwent magnetic resonance imaging (MRI), 99mTc-ECD single-photon emission computed tomography (SPECT) and cognitive testing. Brain tissue type was classified on T1 weighted images, and WMH were identified on interleaved proton density/T2 weighted images. Co-registered MR images were used to characterize SPECT perfusion patterns. RESULTS: WMH perfusion was lower than normal appearing white matter (NAWM) perfusion (P < 0.001) in both EC and AD groups. There was no WMH perfusion difference between groups when considering the mean perfusion from all WMH voxels (P > 0.43). However, locations that were likely to be considered WMH tended to have lower perfusion in ADs compared with ECs. Perfusion gradients along watershed white matter regions were significantly different between EC and AD groups (P < 0.05). A relationship was found between the volume of a WMH lesion and its mean perfusion (P < 0.001) in both ECs and ADs. CONCLUSION: Global WMH were hypoperfused compared with NAWM to the same degree in EC and AD participants, which suggests a common WMH etiology between groups. However, white matter locations that were likely to contain WMH tended to be hypoperfused in ADs compared with healthy aging. This finding is suggestive of AD-specific pathology that reduces the perfusion at anatomic locations susceptible to the formation of WMH through either the neurodegenerative process or AD-related vasculopathy or both.

Feasibility and preliminary efficacy of the LEAD trial: a cluster randomized controlled lifestyle intervention to improve hippocampal volume in older adults at-risk for dementia.

BACKGROUND: Healthy diet and exercise are associated with reduced risk of dementia in older adults. The impact of diet and exercise interventions on brain health is less consistent, especially with dietary interventions which rely on varying approaches. Our objective was to evaluate the feasibility and preliminary efficacy of a 6-month intervention combining exercise with a novel dietary counseling approach to improve hippocampal volume among older adults at-risk for dementia. METHODS: Participants with vascular risk factors and subjective cognitive decline or early mild cognitive impairment were cluster randomized in groups of 3-4 to the diet intervention (DIET) or control education (ED) group. All participants engaged in 1 h of supervised exercise per week and additional exercise at home. DIET involved 1 h per week of group-based dietary counseling comprising education, goal setting, and strategy training. ED involved 1 h per week of group-based brain health education classes. Our primary outcome was change in hippocampal volume from baseline to 6 months. Secondary outcomes included changes in cognitive function, blood biomarkers, diet, and fitness. Recruitment challenges and early discontinuation of the trial due to COVID-19 necessitated a revised focus on feasibility and preliminary efficacy. RESULTS: Of 190 older adults contacted, 14 (7%) were eligible and enrolled, constituting 21% of our recruitment target. All participants completed the intervention and attended 90% of exercise and DIET/ED sessions on average. All 6-month assessments prior to COVID-19 were completed but disruptions to in-person testing resulted in incomplete data collection. No serious adverse events occurred and all participants expressed positive feedback about the study. Preliminary findings did not identify any significant changes in hippocampal volume; however, substantial improvements in diet and HbA1c were observed with DIET compared to ED (d = 1.75 and 1.07, respectively). CONCLUSIONS: High adherence and retention rates were observed among participants and preliminary findings illustrate improvements in diet quality and HbA1c. These results indicate that a larger trial is feasible if difficulties surrounding recruitment can be mitigated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03056508 .

Differential effects of the APOE genotype on brain function across the lifespan.

Increasing age and carrying an APOE ε4 allele are well established risk factors for Alzheimer's disease (AD). The earlier age of onset of AD observed in ε4-carriers may reflect an accelerated aging process. We recently reported that APOE genotype modulates brain function decades before the appearance of any cognitive or clinical symptoms. Here we test the hypothesis that APOE influences brain aging by comparing healthy ε4-carriers and non-carriers, using the same imaging protocol in distinct groups of younger and older healthy volunteers. A cross-sectional factorial design was used to examine the effects of age and APOE genotype, and their interaction, on fMRI activation during an encoding memory task. The younger (N=36; age range 20-35; 18 ε4-carriers) and older (35 middle-age/elderly; age range 50-78 years; 15 ε4-carriers) healthy volunteers taking part in the study were cognitively normal. We found a significant interaction between age and ε4-status in the hippocampi, frontal pole, subcortical nuclei, middle temporal gyri and cerebellum, such that aging was associated with decreased activity in e4-carriers and increased activity in non-carriers. Reduced cerebral blood flow was found in the older ε4-carriers relative to older non-carriers despite preserved grey matter volume. Overactivity of brain function in young ε4-carriers is disproportionately reduced with advancing age even before the onset of measurable memory impairment. The APOE genotype determines age-related changes in brain function that may reflect the increased vulnerability of ε4-carriers to late-life pathology or cognitive decline.

Partial volume correction of multiple inversion time arterial spin labeling MRI data.

The accuracy of cerebral blood flow (CBF) estimates from arterial spin labeling (ASL) is affected by the presence of both gray matter (GM) and white matter within any voxel. Recently a partial volume (PV) correction method for ASL has been demonstrated (Asllani et al. Magn Reson Med 2008; 60:1362-1371), where PV estimates were used with a local linear regression to separate the GM and white matter ASL signal. Here a new PV correction method for multi-inversion time ASL is proposed that exploits PV estimates within a spatially regularized kinetic curve model analysis. The proposed method exploits both PV estimates and the different kinetics of the ASL signal arising from GM and white matter. The new correction method is shown, on both simulated and real data, to provide correction of GM CBF comparable to a linear regression approach, whilst preserving greater spatial detail in the CBF image. On real data corrected GM CBF values were found to be largely independent of GM PV, implying that the correction had been successful. Increases of mean GM CBF after correction of 69-80% were observed.

Optimal pacing strategy: from theoretical modelling to reality in 1500-m speed skating.

PURPOSE: Athletes are trained to choose the pace which is perceived to be correct during a specific effort, such as the 1500-m speed skating competition. The purpose of the present study was to "override" self-paced (SP) performance by instructing athletes to execute a theoretically optimal pacing profile. METHODS: Seven national-level speed-skaters performed a SP 1500-m which was analysed by obtaining velocity (every 100 m) and body position (every 200 m) with video to calculate total mechanical power output. Together with gross efficiency and aerobic kinetics, obtained in separate trials, data were used to calculate aerobic and anaerobic power output profiles. An energy flow model was applied to SP, simulating a range of pacing strategies, and a theoretically optimal pacing profile was imposed in a second race (IM). RESULTS: Final time for IM was ∼2 s slower than SP. Total power distribution per lap differed, with a higher power over the first 300 m for IM (637.0 (49.4) vs 612.5 (50.0) W). Anaerobic parameters did not differ. The faster first lap resulted in a higher aerodynamic drag coefficient and perhaps a less effective push-off. CONCLUSION: Experienced athletes have a well-developed performance template, and changing pacing strategy towards a theoretically optimal fast start protocol had negative consequences on speed-skating technique and did not result in better performance.

Dynamics between psychological distress and body mass index throughout adult life; evidence from 3 large cohort studies.

BACKGROUND: Associations between body mass index (BMI) and psychological distress (PD) have been reported; however, few longitudinal studies have accounted for likely life-course differences in BMI and PD stability, consistency, and their interplay across time. METHODS: Via random intercepts cross-lagged panel models, we assessed the predictive effects (from BMI to PD or vice-versa) across the last two centuries in the Coronary Artery Risk Development in Young Adults [CARDIA, beginning in 1985-6] study using the Center for Epidemiological Studies-Depression Scale [CES-D], and in the National Child Development Study [NCDS, beginning in 1958] and British Cohort Study [BCS, beginning in 1970] using the Malaise Inventory [MI]), assessed at least 4 times in adult life. FINDINGS: In CARDIA (n = 4724), NCDS58 (n = 7149) and BCS70 (n = 5967), autoregressive effects were stronger for BMI than for PD, meaning that carry-over effects from one occasion to the next were larger for BMI than for PD. Small interindividual correlations between traits of higher BMI and higher PD were identified among females (rfemale<|0·2|) but not males (rmale<|0·03|) in CARDIA and NCDS. Cross-lagged effects were very weak or close to zero (standardized effects η<|0·1|). INTERPRETATION: In the United States, depressive symptoms and BMI were positively correlated at the trait level among females. In the United Kingdom, relationships between PD and BMI were inconsistent between generations, with effect sizes of unlikely clinical importance, indicating negligible dominance of an intraindividual effect of BMI on PD or vice versa.

Cerebrovascular Reactivity during Prolonged Breath-Hold in Experienced Freedivers.

BACKGROUND AND PURPOSE: Experienced freedivers can endure prolonged breath-holds despite severe hypoxemia and are therefore ideal subjects to study apnea-induced cerebrovascular reactivity. This multiparametric study investigated CBF, the spatial coefficient of variation as a correlate of arterial transit time and brain metabolism, dynamics during prolonged apnea. MATERIALS AND METHODS: Fifteen male freedivers (age range, 20-64 years; cumulative previous prolonged breath-holds >2 minutes and 30 seconds: 4-79,200) underwent repetitive 3T pseudocontinuous arterial spin-labeling and 31P-/1H-MR spectroscopy before, during, and after a 5-minute breath-hold (split into early and late phases) and gave temporally matching venous blood gas samples. Correlation of temporal and regional cerebrovascular reactivity to blood gases and cumulative previous breath-holds of >2 minutes and 30 seconds in a lifetime was assessed. RESULTS: The spatial coefficient of variation of CBF (by arterial spin-labeling) decreased during the early breath-hold phase (-30.0%, P = .002), whereas CBF remained almost stable during this phase and increased in the late phase (+51.8%, P = .001). CBF differed between the anterior and the posterior circulation during all phases (eg, during late breath-hold: MCA, 57.3 ± 14.2 versus posterior cerebral artery, 42.7 ± 10.8 mL/100 g/min; P = .001). There was an association between breath-hold experience and lower CBF (1000 previous breath-holds reduced WM CBF by 0.6 mL/100 g/min; 95% CI, 0.15-1.1 mL/100 g/min; P = .01). While breath-hold caused peripheral lactate rise (+18.5%) and hypoxemia (oxygen saturation, -24.0%), cerebral lactate and adenosine diphosphate remained within physiologic ranges despite early signs of oxidative stress [-6.4% phosphocreatine / (adenosine triphosphate + adenosine diphosphate); P = .02]. CONCLUSIONS: This study revealed that the cerebral energy metabolism of trained freedivers withstands severe hypoxic hypercarbia in prolonged breath-hold due to a complex cerebrovascular hemodynamic response.

The biphasic force-velocity relationship in whole rat skeletal muscle in situ.

Edman has reported that the force-velocity relationship (FVR) departs from Hill's classic hyperbola near 0.80 of measured isometric force (J Physiol 404: 301-321, 1988). The purpose of this study was to investigate the biphasic nature of the FVR in the rested state and after some recovery from fatigue in the rat medial gastrocnemius muscle in situ. Force-velocity characteristics were determined before and during recovery from fatigue induced by intermittent stimulation at 170 Hz for 100 ms each second for 6 min. Force-velocity data were obtained for isotonic contractions with 100 ms of 200-Hz stimulation, including several measurements with loads above 0.80 of measured isometric force. The force-velocity data obtained in this study were fit well by a double-hyperbolic equation. A departure from Hill's classic hyperbola was found at 0.88+/-0.01 of measured isometric force, which is higher than the approximately 0.80 reported by Edman et al. for isolated frog fibers. After 45 min of recovery, maximum shortening velocity was 86+/-2% of prefatigue, but neither curvature nor predicted isometric force was significantly different from prefatigue. The location of the departure from Hill's classic hyperbola was not different after this recovery from the fatiguing contractions. Including an isometric point in the data set will not yield the same values for maximal velocity and the degree of curvature as would be obtained using the double hyperbola approach. Data up to 0.88 of measured isometric force can be used to fit data to the Hill equation.

Temporal and Spatial Variances in Arterial Spin-Labeling Are Inversely Related to Large-Artery Blood Velocity.

BACKGROUND AND PURPOSE: The relationship between extracranial large-artery characteristics and arterial spin-labeling MR imaging may influence the quality of arterial spin-labeling-CBF images for older adults with and without vascular pathology. We hypothesized that extracranial arterial blood velocity can explain between-person differences in arterial spin-labeling data systematically across clinical populations. MATERIALS AND METHODS: We performed consecutive pseudocontinuous arterial spin-labeling and phase-contrast MR imaging on 82 individuals (20-88 years of age, 50% women), including healthy young adults, healthy older adults, and older adults with cerebral small vessel disease or chronic stroke infarcts. We examined associations between extracranial phase-contrast hemodynamics and intracranial arterial spin-labeling characteristics, which were defined by labeling efficiency, temporal signal-to-noise ratio, and spatial coefficient of variation. RESULTS: Large-artery blood velocity was inversely associated with labeling efficiency (P = .007), temporal SNR (P < .001), and spatial coefficient of variation (P = .05) of arterial spin-labeling, after accounting for age, sex, and group. Correction for labeling efficiency on an individual basis led to additional group differences in GM-CBF compared to correction using a constant labeling efficiency. CONCLUSIONS: Between-subject arterial spin-labeling variance was partially explained by extracranial velocity but not cross-sectional area. Choosing arterial spin-labeling timing parameters with on-line knowledge of blood velocity may improve CBF quantification.

Reports of the length dependence of fatigue are greatly exaggerated.

Relative force depression associated with muscle fatigue is reported to be greater when assessed at short vs. long muscle lengths. This appears to be due to a rightward shift in the force-length relationship. This rightward shift may be caused by stretch of in-series structures, making sarcomere lengths shorter at any given muscle length. Submaximal force-length relationships (twitch, double pulse, 50 Hz) were evaluated before and after repetitive contractions (50 Hz, 300 ms, 1/s) in an in situ preparation of the rat medial gastrocnemius muscle. In some experiments, fascicle lengths were measured with sonomicrometry. Before repetitive stimulation, fascicle lengths were 11.3 +/- 0.8, 12.8 +/- 0.9, and 14.4 +/- 1.2 mm at lengths corresponding to -3.6, 0, and 3.6 mm where 0 is a reference length that corresponds with maximal active force for double-pulse stimulation. After repetitive stimulation, there was no change in fascicle lengths; these lengths were 11.4 +/- 0.8, 12.6 +/- 0.9, and 14.2 +/- 1.2 mm. The length dependence of fatigue was, therefore, not due to a stretch of in-series structures. Interestingly, the rightward shift that was evident when active force was calculated in the traditional way (subtraction of the passive force measured before contraction) was not seen when active force was calculated by subtracting the passive force that was associated with the fascicle length reached at the peak of the contraction. This calculation is based on the assumption that passive force decreases as the fascicles shorten during a fixed-end contraction. This alternative calculation revealed similar postfatigue absolute active force depression at all lengths. In relative terms, a length dependence of fatigue was still evident, but this was greatly diminished compared with that observed when active force was calculated with the traditional method.

Effects of acute aerobic exercise on neural correlates of attention and inhibition in adolescents with bipolar disorder.

Executive dysfunction is common during and between mood episodes in bipolar disorder (BD), causing social and functional impairment. This study investigated the effect of acute exercise on adolescents with BD and healthy control subjects (HC) to test for positive or negative consequences on neural response during an executive task. Fifty adolescents (mean age 16.54±1.47 years, 56% female, 30 with BD) completed an attention and response inhibition task before and after 20 min of recumbent cycling at ~70% of age-predicted maximum heart rate. 3 T functional magnetic resonance imaging data were analyzed in a whole brain voxel-wise analysis and as regions of interest (ROI), examining Go and NoGo response events. In the whole brain analysis of Go trials, exercise had larger effect in BD vs HC throughout ventral prefrontal cortex, amygdala and hippocampus; the profile of these effects was of greater disengagement after exercise. Pre-exercise ROI analysis confirmed this 'deficit in deactivation' for BDs in rostral ACC and found an activation deficit on NoGo errors in accumbens. Pre-exercise accumbens NoGo error activity correlated with depression symptoms and Go activity with mania symptoms; no correlations were present after exercise. Performance was matched to controls and results survived a series of covariate analyses. This study provides evidence that acute aerobic exercise transiently changes neural response during an executive task among adolescents with BD, and that pre-exercise relationships between symptoms and neural response are absent after exercise. Acute aerobic exercise constitutes a biological probe that may provide insights regarding pathophysiology and treatment of BD.

Regional cerebral arterial transit time hemodynamics correlate with vascular risk factors and cognitive function in men with coronary artery disease.

BACKGROUND AND PURPOSE: Arterial transit time is the time needed for blood to travel from large arteries to capillaries, as estimated from arterial spin-labeling MR imaging. The purpose of this study was to determine whether vascular risk factors and cognitive performance are related to regional differences in cerebral arterial transit time in patients with coronary artery disease who are at risk for cognitive decline. MATERIALS AND METHODS: Arterial transit time was estimated from multiple postlabel delay pseudocontinuous arterial spin-labeling images obtained from 29 men with coronary artery disease. Tests of memory, attention, processing speed, and executive function were administered. Principal component analysis was used to create separate models of cognition and vascular risk, which were related to brain regions through voxelwise analyses of arterial transit time maps. RESULTS: Principal component analysis identified 2 components of vascular risk: 1) "pressor" (age, systolic blood pressure, and pulse pressure) and 2) "obesity" (body fat percentage and body mass index). Obesity was inversely related to arterial transit time in the posterior cingulate, precuneus, lateral occipital cortices, middle temporal gyrus, and frontal pole (P corrected < .05), whereas pressor was not significant. Cognitive scores were factored into a single component. Poor performance was inversely related to precuneus arterial transit time (P corrected < .05). The average arterial transit time in regions identified by obesity was associated with poorer cognitive function (r(2) = 0.21, t = -2.65, P = .01). CONCLUSIONS: Altered cerebral hemodynamics, notably in nodal structures of the default mode network, may be one way that vascular risk factors impact cognition in patients with coronary artery disease.

Discovery and spectroscopy of the young jovian planet 51 Eri b with the Gemini Planet Imager.

Directly detecting thermal emission from young extrasolar planets allows measurement of their atmospheric compositions and luminosities, which are influenced by their formation mechanisms. Using the Gemini Planet Imager, we discovered a planet orbiting the ~20-million-year-old star 51 Eridani at a projected separation of 13 astronomical units. Near-infrared observations show a spectrum with strong methane and water-vapor absorption. Modeling of the spectra and photometry yields a luminosity (normalized by the luminosity of the Sun) of 1.6 to 4.0 × 10(-6) and an effective temperature of 600 to 750 kelvin. For this age and luminosity, "hot-start" formation models indicate a mass twice that of Jupiter. This planet also has a sufficiently low luminosity to be consistent with the "cold-start" core-accretion process that may have formed Jupiter.

Production of methionyl-minus ovine growth hormone in Escherichia coli and one-step purification.

The overproduction of ovine growth hormone (oGH) in Escherichia coli is described, achieved in part by alteration of the codon usage for nine of the first 15 amino acids (aa) of the mature hormone. Recombinant oGH (re-oGH), representing 12% of the total cellular protein, was isolated from inclusion bodies by solubilisation using the cationic surfactant cetyltrimethylammonium chloride (CTAC). The hormone was refolded and subsequently purified to greater than 95% homogeneity in a single step using preparative reverse phase high performance liquid chromatography. The aa sequence analysis revealed that the N-terminus of the E. coli-derived polypeptide was identical to that of pituitary-derived oGH, and re-oGH displayed potent somatotropic activity in vivo.

Force-frequency relationship and potentiation in mammalian skeletal muscle.

Repetitive activation of a skeletal muscle results in potentiation of the twitch contractile response. Incompletely fused tetanic contractions similar to those evoked by voluntary activation may also be potentiated by prior activity. We aimed to investigate the role of stimulation frequency on the enhancement of unfused isometric contractions in rat medial gastrocnemius muscles in situ. Muscles set at optimal length were stimulated via the sciatic nerve with 50-micros duration supramaximal pulses. Trials consisted of 8 s of repetitive trains [5 pulses (quintuplets) 2 times per second or 2 pulses (doublets) 5 times per second] at 20, 40, 50, 60, 70, and 80 Hz. These stimulation frequencies represent a range over which voluntary activation would be expected to occur. When the frequency of stimulation was 20, 50, or 70 Hz, the peak active force (highest tension during a contraction - rest tension) of doublet contractions increased from 2.2 +/- 0.2, 4.1 +/- 0.4, and 4.3 +/- 0.5 to 3.1 +/- 0.3, 5.6 +/- 0.4, and 6.1 +/- 0.7 N, respectively. Corresponding measurements for quintuplet contractions increased from 2.2 +/- 0.2, 6.1 +/- 0.5, and 8.7 +/- 0.7 to 3.2 +/- 0.3, 7.3 +/- 0.6, and 9.0 +/- 0.7 N, respectively. Initial peak active force values were 27 +/- 1 and 61.5 +/- 5% of the maximal (tetanic) force for doublet and quintuplet contractions, respectively, at 80 Hz. With doublets, peak active force increased at all stimulation frequencies. With quintuplets, peak active force increased significantly for frequencies up to 60 Hz. Twitch enhancement at the end of the 8 s of repetitive stimulation was the same regardless of the pattern of stimulation during the 8 s, and twitch peak active force returned to prestimulation values by 5 min. These experiments confirm that activity-dependent potentiation is evident during repeated, incompletely fused tetanic contractions over a broad range of frequencies. This observation suggests that, during voluntary motor unit recruitment, derecruitment or decreased firing frequency would be necessary to achieve a fixed (submaximal) target force during repeated isometric contractions over this time period.

Length dependence of active force production in skeletal muscle.

The sliding filament and cross-bridge theories of muscle contraction provide discrete predictions of the tetanic force-length relationship of skeletal muscle that have been tested experimentally. The active force generated by a maximally activated single fiber (with sarcomere length control) is maximal when the filament overlap is optimized and is proportionally decreased when overlap is diminished. The force-length relationship is a static property of skeletal muscle and, therefore, it does not predict the consequences of dynamic contractions. Changes in sarcomere length during muscle contraction result in modulation of the active force that is not necessarily predicted by the cross-bridge theory. The results of in vivo studies of the force-length relationship suggest that muscles that operate on the ascending limb of the force-length relationship typically function in stretch-shortening cycle contractions, and muscles that operate on the descending limb typically function in shorten-stretch cycle contractions. The joint moments produced by a muscle depend on the moment arm and the sarcomere length of the muscle. Moment arm magnitude also affects the excursion (length change) of a muscle for a given change in joint angle, and the number of sarcomeres arranged in series within a muscle fiber determines the sarcomere length change associated with a given excursion.

Skeletal muscle staircase response with fatigue or dantrolene sodium.

It has been postulated that the staircase response of skeletal muscle is effected by Ca2+-dependent phosphorylation of myosin light chains. Dantrolene inhibits calcium release from the sarcoplasmic reticulum, so treatment with dantrolene should prolong the time required to reach the peak of the staircase response. Furthermore, since it has been postulated that Ca2+ release is attenuated by fatigue, there should be similarities between the staircase of fatigued muscle and staircase in the presence of dantrolene. The left gastrocnemius muscle of anesthetized rats was isolated in situ and connected to an isometric transducer. In the control condition, developed tension increased for approximately 10 s with repetitive stimulation at 10 Hz. The time to reach the peak of staircase was prolonged after a 5 min period of stimulation at 10 Hz or after injection of dantrolene sodium (0.8 mg.kg-1 IV). Other similarities between the dantrolene treated group and the fatigue group include the following: contraction time was shorter in fatigue (12.8 +/- 0.8 ms) and with dantrolene (14.7 +/- 1.3 ms) than in the controls (16.4 +/- 1 ms), and half-relaxation time increased from 5 s (10.8 +/- 9 ms) to 15 s (13.8 +/- 0.8 ms) of staircase in the control but did not increase at this time in the dantrolene or fatigue groups. This study demonstrates that both fatigue and a reduction in Ca2+ release from sarcoplasmic reticulum will prolong the time required to reach the peak of staircase.