Sarcomere length changes during end-held (isometric) contractions in intact mammalian (rat) fast and slow muscle fibres

The sarcomere length change, within a 2 mm region, during end-held isometric contractions in intact rat fast and slow muscle fibre bundles was investigated at 20°C and an initial sarcomere length of 2.68 m using He–Ne laser diffraction. In some experiments, the fibre segment displacement was monitored with markers (pieces of human hair) placed at regular intervals on the surface of the muscle fibre bundles. The sarcomere length changes, monitored near the proximal end of the bundle (transducer end), during tetanic contractions were similar to those previously reported in frog muscle fibres. Thus, throughout the tension plateau, sarcomere length remained constant (and shortened) but showed evidence of non-uniform sarcomere behaviour (further shortening) during the rapid tension relaxation phase. Such non-uniform behaviour was not seen during twitch contractions. During a twitch contraction, sarcomeres at the proximal end shortened rapidly at first and continued to shorten – or remained shortened – until the tension had relaxed to between 20–23% of its peak value before lengthening back to the original length. The maximum twitch sarcomere shortening (mean ± SEM) was 5.9 ± 0.2% (n = 16) in fast and 5.4 ± 0.3% (n = 14) in slow fibre bundles at 20°C; sarcomere shortening near body temperature (35°C) was greater, 8.8 ± 0.2% (n = 7) in fast and 8.1 ± 0.2% (n = 5) in slow fibre bundles. Increasing the initial sarcomere length of a preparation decreased the extent of sarcomere shortening and reducing the amount of sarcomere shortening, by sarcomere length clamping, markedly increased the peak twitch tension without significantly altering the twitch time course. When examined at different positions along muscle fibres, a sarcomere shortening was observed along much of the fibre length in most preparations. However, in about a third of the preparations some sarcomere lengthening was recorded in the distal end, but its amplitude was too small to accommodate the fibre shortening elsewhere. Complementary data were obtained using the surface marker technique. The displacement was largest and in opposite – but fibre shortening – direction in the markers placed 0.5–1.0 mm away from the two tendon attachments; the markers placed at or near the centre of the fibre bundle showed the least amount of displacement. The findings suggest that the compliant region, where lengthening occurs, is at fibre ends, i.e. near myotendinous junction.     

Pressure-induced changes in the isometric contractions of single intact frog muscle fibres at low temperatures

Summary Effects of increased hydrostatic pressure (range 0.1–10 MPa) on isometric twitch and tetanic contractions of single intact muscle fibres, isolated from frog tibialis anterior muscle, were examined at 4–12° C. The tension changes produced on exposure to steady high pressures are compared with those produced on exposure to low concentrations of caffeine (0.5 mm, subthreshold for contracture) and when pressure is rapidly released during a contraction. The peak twitch tension was potentiated by pressure accompanied by increased rate of tension rise and increased duration; the pressure sensitivity of twitch tension was 8% mPa^-1. The correlation between the rate of tension rise and peak tension in caffeine-induced twitch tension potentiation was quantitatively similar to that in pressure-induced twitch potentiation. Experiments involving the rapid release of pressure (2 ms) during twitch contractions demonstrate that high pressure need only be maintained for a brief period during the early part of tension development to elicit full twitch potentiation. The tetanic tension was depressed by pressure (1% MPa^-1). Results demonstrate that the major effect of increased hydrostatic pressure on intact muscle fibres, which results in tension potentiation, is complete very early during contraction and is similar to that of caffeine.     

The role of graft reperfusion sequence in the development of non-anastomotic biliary strictures following orthotopic liver transplantation: A meta-analysis

Background

Liver transplant is a potential cure for liver failure and hepatic malignancy but there are many techniques which have been described for vascular reconstruction. This study was to compare the prevalence of non-anastomotic biliary stricture and other surgical complications based on Clavien-Dindo scoring system, in initial portal reperfusion (sequential) versus simultaneous or initial artery reperfusion.

Disease-modifying effects of edasalonexent,an NF-κB inhibitor,in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial

Chronic activation of NF-κB is a key driver of muscle degeneration and suppression of muscle regeneration in Duchenne muscular dystrophy. Edasalonexent (CAT-1004) is an orally-administered novel small molecule that covalently links two bioactive compounds (salicylic acid and docosahexaenoic acid) that inhibit NF-κB. This placebo-controlled, proof-of-concept phase 2 study with open-label extension in boys ≥4-<8 years old with any dystrophin mutation examined the effect of edasalonexent (67 or 100 mg/kg/day) compared to placebo or off-treatment control. Endpoints were safety/tolerability, change from baseline in MRI T₂ relaxation time of lower leg muscles and functional assessment, as well as pharmacodynamics and biomarkers. Treatment was well-tolerated and the majority of adverse events were mild, and most commonly of the gastrointestinal system (primarily diarrhea). There were no serious adverse events in the edasalonexent groups. Edasalonexent 100 mg/kg was associated with slowing of disease progression and preservation of muscle function compared to an off-treatment control period, with decrease in levels of NF-κB-regulated genes and improvements in biomarkers of muscle health and inflammation. These results support investigating edasalonexent in future trials and have informed the design of the edasalonexent phase 3 clinical trial in boys with Duchenne.     

Apoptotic U1-70 kd is antigenically distinct from the intact form of the U1-70-kd molecule

OBJECTIVE: To determine whether immune responses to an apoptotically modified form of a human lupus autoantigen can be distinguished from immune responses to the intact form of the same antigen. METHODS: Immunoblot and enzyme-linked immunosorbent assay techniques were used to test human autoimmune sera for the presence of antibodies to apoptotic forms of the U1- 70-kd small nuclear RNP antigen, while antibody recognition of intact U1-70 kd was blocked. RESULTS: poptosis-specific U1-70-kd antibodies were identified by immunoblot in 15 of 29 sera with antibodies to intact U1-70 kd and in 2 of 25 sera without measurable antibodies to intact U1-70 kd. Bacterially produced, purified, caspase-cleaved U1-70 kd without additional posttranslational modifications was a target of apoptosis-specific antibodies in 3 of 9 U1-70-kd-positive sera tested. CONCLUSION: The apoptotic form of U1-70 kd displays B cell epitopes that are not displayed on the intact form of U1-70 kd. Caspase cleavage in the absence of additional posttranslational modifications is sufficient to induce the display of some of these epitopes. Immunity to apoptotically modified proteins can develop against caspase-cleaved forms or against forms that undergo additional posttranslational modification.