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Past contraction-induced skeletal muscle injury reduces the degree of subsequent injury; this phenomenon is called the "repeated bout effect (RBE)." This study addresses the mechanisms underlying the RBE, focusing on primary calcium-dependent injury pathways. Wistar rats were subdivided into single injury (SI) and repeated injury (RI) groups. At age 10 weeks, the right gastrocnemius muscle in each rat in the RI group was subjected to strenuous eccentric contractions (ECs). Subsequently, mild ECs were imposed on the same muscle of each rat at 14 weeks of age in both groups. One day after the exercise, the RI group showed a lower strength deficit than did the SI group, and neither group manifested any increase in membrane permeability. The concentration of protein carbonyls and activation of total calpain increased after ECs given at the age of 14 weeks. Nonetheless, these increases were lower in the RI group than in the SI group. Furthermore, calcium-dependent autolysis of calpain-1 and calpain-3 in the RI group was diminished as compared with that in the SI group. Although peak ankle joint torque and total force generation during ECs at the age of 14 weeks were similar between the two groups, phosphorylation of JNK (Thr 183 /Tyr 185 ), an indicator of mechanical stress applied to a muscle, was lower in the RI group than in the SI group. These findings suggest that activation of the primary calcium-dependent injury pathways is attenuated by past injurious exercise, and mechanical stress applied to muscle fibers during ECs may decrease in the RBE., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

We compared the skeletal muscle hypertrophy resulting from isometric (Iso) or eccentric (Ecc) electrical stimulation (ES) training with different stimulation frequencies. Male Wistar rats were assigned to the Iso and Ecc groups. These were divided into three further subgroups that were stimulated at 10 Hz (Iso-10 and Ecc-10), 30 Hz (Iso-30 and Ecc-30), or 100 Hz (Iso-100 and Ecc-100). In experiment 1, the left plantarflexor muscles were stimulated every other day for 3 wk. In experiment 2, mammalian target of rapamycin complex 1 (mTORC1) signaling was investigated 6 h after one bout of ES. The contralateral right muscle served as a control (non-ES). Ecc contractions comprised forced dorsiflexion combined with ES. The peak torque and torque-time integral during ES were higher in the Ecc group than that in the Iso group in all stimulation frequencies examined. The gastrocnemius muscle weight normalized to body weight in ES side was increased compared with the non-ES side by 6, 7, and 17% in the Ecc-30, Iso-100, and Ecc-100 groups, respectively, with a greater gain in Ecc-100 than the Ecc-30 and Iso-100 groups. The p70S6K (Thr389) phosphorylation level was higher in the Ecc-30 and -100 than in the Iso-30 and -100 groups, respectively. The peak torque and torque-time integral were highly correlated with the magnitude of increase in muscle mass and the phosphorylation of p70S6K. These data suggest that ES-induced muscle hypertrophy and mTORC1 activity are determined by loading intensity and volume during muscle contraction independent of the contraction mode. NEW & NOTEWORTHY Eccentric contraction and high-frequency stimulation (HFS) are regarded as an effective way to increase muscle mass by electrical stimulation (ES) training. However, little is known about whether muscle hypertrophy is affected by contraction mode and stimulation frequency in ES training. Here, we provide the evidence that muscle hypertrophy and mammalian target of rapamycin complex 1 activity are determined by mechanical loading during contraction but not on the contraction mode itself, with a greater gain at HFS.

We investigated the influence of past injurious exercise on anabolic response of skeletal muscle fibers to resistance exercise (RE). Wistar rats were divided into exercise (E) and exercise-after-injury (I-E) groups. At age 10 wk, the right gastrocnemius muscle in each rat in the I-E group was subjected to strenuous eccentric contractions. Subsequently, RE was imposed on the same muscle of each rat at 14 wk of age in both groups. Peak joint torque and total force generation per body mass during RE were similar between the groups. Muscle protein synthesis (MPS) in the I-E group was higher than that in the E group 6 h after RE. Furthermore, levels of phospho-p70S6 kinase (Thr 389 ) and phospho-ribosomal protein S6 (phospho-rpS6) (Ser 240/244 ), a downstream target of p70S6 kinase, were higher in the I-E group than in the E group. For the anabolic response in each fiber type, the I-E group showed a higher MPS response in type IIb, IIa, and I fibers and a higher phospho-rpS6 response in type IIx, IIa, and I fibers than the E group. In the I-E group, the relative content of myosin heavy chain (MHC) IIa was higher and that of MHC IIb was lower than those in the E group. In addition, type IIa fibers showed a lower MPS response to RE than type IIb fibers in the I-E group. In conclusion, the past injurious exercise enhanced the MPS and phospho-rpS6 responses in type IIb, IIa, and I fibers and type IIx, IIa, and I fibers, respectively. NEW & NOTEWORTHY Past injurious exercise increased the muscle protein synthesis (MPS) response and mammalian target of rapamycin complex 1 (mTORC1) signaling activation to resistance exercise. In the responses of each fiber type, the past injurious exercise increased the MPS and phosphorylation ribosomal protein (Ser 240/244 ) responses in type IIb, IIa, and I fibers and type IIx, IIa, and I fibers, respectively.

The intestinal microbial ecosystem is actively regulated by Paneth cell-derived antimicrobial peptides such as α-defensins. Various disorders, including graft-versus-host disease (GVHD), disrupt Paneth cell functions, resulting in unfavorably altered intestinal microbiota (dysbiosis), which further accelerates the underlying diseases. Current strategies to restore the gut ecosystem are bacteriotherapy such as fecal microbiota transplantation and probiotics, and no physiological approach has been developed so far. In this study, we demonstrate a novel approach to restore gut microbial ecology by Wnt agonist R-Spondin1 (R-Spo1) or recombinant α-defensin in mice. R-Spo1 stimulates intestinal stem cells to differentiate to Paneth cells and enhances luminal secretion of α-defensins. Administration of R-Spo1 or recombinant α-defensin prevents GVHD-mediated dysbiosis, thus representing a novel and physiological approach at modifying the gut ecosystem to restore intestinal homeostasis and host-microbiota cross talk toward therapeutic benefits., (© 2017 Hayase et al.)

The recovery period between bouts of exercise is one of the major factors influencing the effects of resistance exercise, in addition to exercise intensity and volume. However, the effects of shortening the recovery time between bouts of resistance exercise on subsequent protein synthesis remain unclear. In this study, we investigated the consequences of shortening the recovery time between bouts of resistance exercise on protein synthesis and related processes in mouse skeletal muscles. Eighteen male C57BL/6J mice were randomly subjected to three bouts of resistance exercise with 72 (72H), 24 (24H), or 8 h (8H) of recovery periods between bouts. Resistance exercise, consisting of five sets of 3 s × 10 isometric contractions with 3 min rest between sets, was elicited on the right tibialis anterior muscle via percutaneous electrical stimulation on the deep peroneal nerve under isoflurane anesthesia. The left muscle served as an internal control. Six hours after the third bout of exercise, protein synthesis was found to be activated in the 72H and 24H groups, but not in the 8H group. Phosphorylation of p70S6K at Thr 389, a marker of mammalian target of rapamycin (mTOR) signaling, was increased in all groups, with the 8H group showing the highest magnitude. In contrast, protein carbonylation was observed only in mice in the 8H group. These results suggest that repeated bouts of resistance exercise with 8 h of recovery periods do not effectively increase the levels of muscle protein synthesis despite activation of the mTOR signaling pathway, which likely involves oxidative stress., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Resistance exercise (RE) volume is recognized as an important factor that stimulates muscle protein synthesis (MPS) and is considered, at least in part, to be involved in the mammalian target of rapamycin complex 1 (mTORC1)-associated signaling. However, the effects of relatively high-volume RE on mTORC1 and MPS remain unclear. In the present study, we used an animal model of RE to investigate the relationship between RE volume and MPS. Male Sprague-Dawley rats were subjected to RE, and muscle samples were obtained 6 h after performing 1, 3, 5, 10, or 20 sets of RE. Although 1 set of RE did not increase MPS [measured by the surface sensing of translation (SUnSET) method], multiple sets (3, 5, 10, and 20 sets) significantly increased MPS. However, the increase in MPS reached a plateau after 3 or 5 sets of RE, and no further increase in MPS was observed with additional RE sets. In contrast to the MPS response, we observed that p70S6K phosphorylation at Thr389, a marker of mTORC1 activity, and Ser240/244 phosphorylation of rpS6, a downstream target of p70S6K, gradually increased with higher RE volume. The above results suggest that the relationship between RE volume and MPS was not linear. Thus the increase in MPS with increasing RE volume saturates before p70S6K phosphorylation, suggesting a threshold effect for the relationship between p70S6K activation and MPS. NEW & NOTEWORTHY The aim of this study was to investigate the relationship between resistance exercise (RE) volume and muscle protein synthesis. We found that the relationship between RE volume and p70S6K phosphorylation was almost linear, but the increase in muscle protein synthesis began to plateau after approximately five sets of RE., (Copyright © 2017 the American Physiological Society.)

Infertility associated with ovarian failure is a serious late complication for female survivors of allogeneic hematopoietic stem cell transplantation (SCT). Although pretransplant conditioning regimen has been appreciated as a cause of ovarian failure, increased application of reduced-intensity conditioning allowed us to revisit other factors possibly affecting ovarian function after allogeneic SCT. We have addressed whether donor T-cell-mediated graft-versus-host disease (GVHD) could be causally related to female infertility in mice. Histological evaluation of the ovaries after SCT demonstrated donor T-cell infiltration in close proximity to apoptotic granulosa cells in the ovarian follicles, resulting in impaired follicular hormone production and maturation of ovarian follicles. Mating experiments showed that female recipients of allogeneic SCT deliver significantly fewer newborns than recipients of syngeneic SCT. GVHD-mediated ovary insufficiency and infertility were independent of conditioning. Pharmacologic GVHD prophylaxis protected the ovary from GVHD and preserved fertility. These results demonstrate for the first time that GVHD targets the ovary and impairs ovarian function and fertility and has important clinical implications in young female transplant recipients with nonmalignant diseases, in whom minimally toxic regimens are used., (© 2017 by The American Society of Hematology.)

Dietary protein intake is critical for maintaining an optimal muscle mass, especially among older individuals. Although protein supplementation during resistance training (RT) has been shown to further augment training-induced muscle mass in older individuals, the impact of daily variations in protein intake on training-induced muscle mass has not been explored thus far. Therefore, this study aimed to investigate the relationship between the dietary protein and amino acid intake and RT-induced muscle hypertrophy among older individuals. Ten healthy older men (n=10; mean age=69±2 y; body weight (BW)=61.5±2.2 kg; height=1.65±0.02 m) participated in progressive RT performed 3 times/wk for 12 wk. Body composition (using DXA) and nutritional assessments (using a 3-d dietary record) were performed before and after the training period. Leg lean mass (LLM) increased significantly (15.0±0.8 vs. 15.4±0.8 kg, p<0.05) after RT, with no change in dietary nutrient intake. The average dietary protein intake was 1.62±0.11 g/kg BW/d, while essential amino acids was 600±51 mg/kg BW/d. Although the correlation between the increase in LLM and dietary protein intake was not significant, a significant correlation was found between the increase in LLM and dietary essential amino acid (EAA) intake. Furthermore, there were significant correlations between the increase in LLM and protein as well as EAA (especially leucine) intake at breakfast among subjects with suboptimal protein intake (p<0.05). Our study findings indicate that dietary protein as well as EAA intake may be significant contributing factors in muscle hypertrophic response during RT among healthy older men.

This study investigated the injured region-specific alterations of factors related to the "repeated bout effect" (RBE), i.e., when the first bout of eccentric exercise generates resistance to injuries from the second bout of the same exercise. Wistar rats were divided into single injury (SI) and repeated injury (RI) groups. The right gastrocnemius muscle was subjected to a bout of eccentric contractions (ECs) at the age of 14 weeks in the SI group and 10 and 14 weeks in the RI group. The number of injured fibers after the last bout of ECs was lower in RI than in SI. In the SI group, injured fibers after ECs were mainly located in the superficial region of muscle and expressed myosin heavy chain (MHC) IIx and IIb. Prior to the second bout of ECs, the fiber-type composition in the RI group showed decreased MHC IIx and IIb fibers and increased MHC IIa fibers compared with those in the SI group. However, most regenerating fibers showed either MHC IIx or IIb expression. Heat shock protein 72 and total collagen contents in whole muscle were higher in the RI group than in the SI group; however, only the collagen expression in the RI group was more intense than that in the SI group in the superficial region of muscle. These findings suggest that increased collagen may play a more important role in the injured region of muscle than the other factors in RBE.

Recent studies have demonstrated that resistance exercise leads not only to muscle hypertrophy, but it also improves mitochondrial function. Because calorie restriction (CR) has been suggested as a way to induce mitochondrial biogenesis, we examined the effects of resistance training with or without CR on muscle weight and key mitochondrial parameters in rat skeletal muscle. Four weeks of resistance training (thrice/wk) resulted in increased gastrocnemius muscle weight by 14% in rats fed ad libitum (AL). The degree of muscle-weight increase via resistance training was lower in rats with CR (7.4%). CR showed no effect on phosphorylation of mammalian target of rapamycin (mTOR) signaling proteins rpS6 and ULK1. Our results revealed that CR resulted in elevated levels of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) protein, a known master regulator of mitochondrial biogenesis. Resistance training alone also resulted in increased PGC-1α levels in skeletal muscle. The magnitude of the increase in PGC-1α was similar in rats in both the CR and AL groups. Moreover, we found that resistance training with CR resulted in elevated levels of proteins involved in mitochondrial fusion (Opa1 and Mfn1), and oxidative phosphorylation, whereas there was no effect of CR on the fission-regulatory proteins Fis1 and Drp1. These results indicate that CR attenuates resistance training-induced muscle hypertrophy, and that it may enhance mitochondrial adaptations in skeletal muscle., (Copyright © 2016 the American Physiological Society.)

Resistance exercise (RE) activates signalling by the mammalian target of rapamycin (mTOR), and it has been suggested that rapamycin-sensitive mTOR signalling controls RE-induced changes in protein synthesis, ribosome biogenesis, autophagy, and the expression of peroxisome proliferator gamma coactivator 1 alpha (PGC-1α). However, direct evidence to support the aforementioned relationships is lacking. Therefore, in this study, we investigated the role of rapamycin-sensitive mTOR in the RE-induced activation of muscle protein synthesis, ribosome biogenesis, PGC-1α expression and hypertrophy. The results indicated that the inhibition of rapamycin-sensitive mTOR could prevent the induction of ribosome biogenesis by RE, but it only partially inhibited the activation of muscle protein synthesis. Likewise, the inhibition of rapamycin-sensitive mTOR only partially blocked the hypertrophic effects of chronic RE. Furthermore, both acute and chronic RE promoted an increase in PGC-1α expression and these alterations were not affected by the inhibition of rapamycin-sensitive mTOR. Combined, the results from this study not only establish that rapamycin-sensitive mTOR plays an important role in the RE-induced activation of protein synthesis and the induction of hypertrophy, but they also demonstrate that additional (rapamycin-sensitive mTOR-independent) mechanisms contribute to these fundamentally important events.

Extracellular superoxide dismutase (EC-SOD) is one of the main SOD isozymes and plays an important role in the prevention of cardiovascular diseases by accelerating the dismutation reaction of superoxide. Royal jelly includes 10-hydroxy-2-decenoic acid (10H2DA, 2), which regulates the expression of various types of genes in epigenetics through the effects of histone deacetylase (HDAC) antagonism. The expression of EC-SOD was previously reported to be regulated epigenetically through histone acetylation in THP-1 cells. Therefore, we herein evaluated the effects of the royal jelly constituents 10-hydroxydecanoic acid (10HDA, 1), sebacic acid (SA, 3), and 4-hydroperoxy-2-decenoic acid ethyl ester (4-HPO-DAEE, 4), which is a derivative of 2, on the expression of EC-SOD in THP-1 cells. The treatment with 1 mM 1, 2, or 3 or 100 μM 4 increased EC-SOD expression and histone H3 and H4 acetylation levels. Moreover, the enrichment of acetylated histone H4 was observed in the proximal promoter region of EC-SOD and was caused by the partial promotion of ERK phosphorylation (only 4) and inhibition of HDAC activities, but not by the expression of HDACs. Overall, 4 exerted stronger effects than 1, 2, or 3 and has potential as a candidate or lead compound against atherosclerosis.

Large variability exists in muscle adaptive response to resistance exercise (RE) training between individuals. Recent studies have revealed a significant role for microRNAs (miRNAs) in skeletal muscle plasticity. In this study, we investigated how RE affects miRNA expression and whether the variability of muscle hypertrophy to RE training may be attributed to differential miRNA regulation in the skeletal muscle. To screen high and low responders to RE, we had 18 young men perform arm curl exercise training. After screening, all the men performed 12 wk of lower body RE training, but only the high or low responders participated in the acute RE test before training. Muscle biopsies were obtained from the vastus lateralis muscle at baseline, 3 h after acute RE, and after the training period. Total RNA was extracted from the skeletal muscle, and miRNA expression (800 miRNAs) was analyzed. RE training increased the cross-sectional area of the biceps brachii (-1.7-26.1%), quadriceps (2.2-16.8%), and hamstrings (1.6-18.4%). Eighty-five and 102 miRNAs were differentially expressed after acute and chronic RE, respectively (P < 0.05). Seventeen miRNAs, especially 23b-3p, 26a-5p, 32-5p, 148b-3p, and 376a-3p, were differentially expressed at baseline, and 23 miRNAs, especially let-7a-5p, 95, 148a-3p, and 376a-3p, and 26 miRNAs, especially 30d-5p and 376a-3p, were differentially regulated after acute and chronic RE, respectively, in the skeletal muscle between high and low responders, indicating that the expression patterns of several miRNAs are altered by acute or chronic RE, and that miRNAs are involved in skeletal muscle adaptation to RE training., (Copyright © 2016 the American Physiological Society.)

External loads applied to skeletal muscle cause increases in the protein translation rate, which leads to muscle hypertrophy. Although some studies have demonstrated that increases in the capacity and efficiency of translation are involved in this process, it remains unclear how these two factors are related to the magnitude of muscle hypertrophy. The present study aimed to clarify the roles played by the capacity and efficiency of translation in muscle hypertrophy. We used an improved synergist ablation in which the magnitude of compensatory hypertrophy could be controlled by partial removal of synergist muscles. Male rats were assigned to four groups in which the plantaris muscle was unilaterally subjected to weak (WK), moderate (MO), middle (MI), and strong (ST) overloading by four types of synergist ablation. Fourteen days after surgery, the weight of the plantaris muscle per body weight increased by 8%, 22%, 32% and 45%, in the WK, MO, MI and ST groups, respectively. Five days after surgery, 18+28S rRNA content (an indicator of translational capacity) increased with increasing overload, with increases of 1.8-fold (MO), 2.2-fold (MI), and 2.5-fold (ST), respectively, relative to non-overloaded muscle (NL) in the WK group. rRNA content showed a strong correlation with relative muscle weight measured 14 days after surgery (r = 0.98). The phosphorylated form of p70S6K (a positive regulator of translational efficiency) showed a marked increase in the MO group, but no further increase was observed with further increase in overload (increases of 22.6-fold (MO), 17.4-fold (MI), and 18.2-fold (ST), respectively, relative to NL in the WK group). These results indicate that increases in ribosome biogenesis at the early phase of overloading are strongly dependent on the amount of overloading, and may play an important role in increasing the translational capacity for further gain of muscular size.

It is well known that resistance exercise increases muscle protein synthesis and muscle strength. However, little is known about the effect of resistance exercise on mitochondrial dynamics, which is coupled with mitochondrial function. In skeletal muscle, mitochondria exist as dynamic networks that are continuously remodeling through fusion and fission. The purpose of this study was to investigate the effect of acute and chronic resistance exercise, which induces muscle hypertrophy, on the expression of proteins related to mitochondrial dynamics in rat skeletal muscle. Resistance exercise consisted of maximum isometric contraction, which was induced by percutaneous electrical stimulation of the gastrocnemius muscle. Our results revealed no change in levels of proteins that regulate mitochondrial fission (Fis1 and Drp1) or fusion (Opa1, Mfn1, and Mfn2) over the 24-h period following acute resistance exercise. Phosphorylation of Drp1 at Ser616 was increased immediately after exercise (P < 0.01). Four weeks of resistance training (3 times/week) increased Mfn1 (P < 0.01), Mfn2 (P < 0.05), and Opa1 (P < 0.01) protein levels without altering mitochondrial oxidative phosphorylation proteins. These observations suggest that resistance exercise has little effect on mitochondrial biogenesis but alters the expression of proteins involved in mitochondrial fusion and fission, which may contribute to mitochondrial quality control and improved mitochondrial function.

New Findings: What is the central question of this study? Does an acute bout of exercise alter vitamin D receptor expression in rat skeletal muscle? What is the main finding and its importance? Resistance exercise but not endurance exercise increased intramuscular vitamin D receptor expression. Thus, resistance exercise may be an effective way to increase muscle vitamin D receptor expression. Vitamin D and vitamin D receptor (VDR) are involved in the maintenance of skeletal muscle mass and function. Although resistance exercise is well known to enhance muscle growth and improve muscle function, the effect of resistance exercise on VDR has been unclear. We investigated intramuscular VDR expression in response to an acute bout of resistance exercise or endurance exercise. Male adult Sprague-Dawley rats were subjected to either resistance exercise (isometrically exercised via percutaneous electrical stimulation for five sets of ten 3 s contractions, with a 7 s interval between contractions and 3 min rest intervals between sets) or endurance exercise (treadmill at 25 m min(-1) for 60 min). Rats were killed immediately or 1, 3, 6 or 24 h after completion of the resistance or endurance exercise, and gastrocnemius muscles were removed. Non-exercised control animals were killed in a basal state (control group). Intramuscular VDR expression was significantly higher immediately after resistance exercise and elevated for 3 h after exercise compared with the control group (P < 0.05), and the resistance exercise significantly increased phosphorylated ERK1/2 and Mnk1 expression (P < 0.05), which may be associated with VDR expression, immediately after exercise. Additionally, intramuscular expression of cytochrome P450 27B1, an enzyme related to vitamin D metabolism, was significantly higher at 1 and 3 h after exercise (P < 0.05) compared with the control group. In contrast, endurance exercise had no effect on any of the measured proteins. Our results indicate that resistance exercise may be an efficient way to increase intramuscular VDR and related enzyme expression., (© 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.)

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for various hematopoietic disorders. Graft-versus-host disease (GVHD) and infections are the major obstacles of HSCT, and their close relationship has been suggested. Although roles of bacterial and viral infections in the pathophysiology of GVHD are well described, impacts of fungal infection on GVHD remain to be elucidated. In mouse models of GVHD, injection of α-mannan (Mn), a major component of fungal cell wall, or heat-killed Candida albicans exacerbated GVHD, particularly in the lung. Mn-induced donor T-cell polarization toward Th17 and lung-specific chemokine environment in GVHD led to accumulation of Th17 cells in the lung. The detrimental effects of Mn on GVHD depended on donor IL-17A production and host C-type lectin receptor Dectin-2. These results suggest a previously unrecognized link between pulmonary GVHD and fungal infection after allogeneic HSCT., (© 2015 by The American Society of Hematology.)

We investigated the effects of 3 weeks of detraining on muscle cross-sectional area (CSA) and one-repetition maximum strength (1-RM) in young men who had previously participated in 6 weeks (3 days week(-1) ) of bench press training [blood flow restricted low-intensity (LI-BFR; n = 10, 20% 1-RM) or high-intensity (HI; n = 7, 75% 1-RM)]. Bench press 1-RM and muscle CSA of triceps brachii (TB) and pectoralis major (PM) were evaluated before (pre) and after training period (post) as well as after detraining period (detraining). Bench press 1-RM was higher at both post and detraining than at pre for LI-BFR (P<0·01) and the HI (P<0·01). TB and PM muscle CSA were higher at both post and detraining than at pre for the HI group (P<0·01), while the LI-BFR group only increased (P<0·01) at post. Relative dynamic strength (1-RM divided by TB muscle CSA) was higher at both post and detraining than at pre for the HI group (P<0·01), while the LI-BFR group only increased (P<0·01) at detraining. In conclusion, increased muscle strength following 6 weeks of training with LI-BFR as well as HI was well preserved at 3 weeks of detraining. HI-induced muscle strength appears to be dependent upon both neural adaptations and muscle hypertrophy with training and detraining. On the other hand, LI-BFR-induced muscle strength appears to be related primarily to muscle hypertrophy with training and to neural adaptations with detraining., (© 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Recent studies indicate that matrix metalloproteinases (MMPs) and critical linkage proteins in the extracellular matrix (ECM) regulate skeletal muscle mass, although the effects of resistance training (RT) on protein expression and activity are unclear. Thus, the purpose of the present study was to investigate the effects of RT on MMP activity and expression of ECM-related proteins. Ten male Sprague-Dawley rats were randomly assigned to 1 bout (1B) or 18 bouts (18B) of electrical stimulation. The right gastrocnemius muscle was isometrically contracted via percutaneous electrical stimulation (five sets of 5 sec stimulation × five contractions/set with 5 sec interval between contractions and 3 min rest between sets) once (1B) or every other day for 5 weeks (18B). The left leg served as a control. Activity of MMP-2 and MMP-9, determined via gelatin zymography, was increased (P < 0.05) immediately after 1B. However, MMP activation was not evident following 18B. No changes in collagen IV, laminin α2, α7-integrin, or ILK protein expression were detected immediately following 1B or 18B. However, β1-integrin protein expression was significantly increased (P < 0.05) with 18B. Our results suggest that resistance exercise activates MMPs during the initial phase of RT but this response is attenuated with continuation of RT., (© 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

We previously reported that low-intensity [50% of one repetition maximum (1RM)] resistance training with slow movement and tonic force generation (LST) causes muscle hypertrophy and strength gain in older participants. The aim of this study was to determine whether resistance training with slow movement and much more reduced intensity (30%1RM) increases muscle size and strength in older adults. Eighteen participants (60-77 years) were randomly assigned to two groups. One group performed very low-intensity (30% 1RM) knee extension exercise with continuous muscle contraction (LST: 3-s eccentric, 3-s concentric, and 1-s isometric actions with no rest between each repetition) twice a week for 12 weeks. The other group underwent intermitted muscle contraction (CON: 1-s concentric and 1-s eccentric actions with 1-s rest between each repetition) for the same time period. The 1RM, isometric and isokinetic strengths, and cross-sectional image of the mid-thigh obtained by magnetic resonance imaging were examined before and after the intervention. LST significantly increased the cross-sectional area of the quadriceps muscle (5.0%, P<0.001) and isometric and isokinetic knee extension strengths (P<0.05). CON failed to increase muscle size (1.1%, P = 0.12), but significantly improved its strength (P<0.05). These results indicate that even if the intensity is as low as 30% 1RM, LST can increase muscle size and strength in healthy older adults. The large total contraction time may be related to muscle hypertrophy and strength gain. LST would be useful for preventing sarcopenia in older individuals., (© 2013 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

In the reversed clinicopathological conference (R-CPC), we analyzed a patient's pathosis using only the results of routine laboratory tests. R-CPC is one of the most effective training methods to acquire the abil- ity to interpret such data logically and reasonably. At the same time, we can know the limits of laboratory data, even though they can be analyzed in detail. In this R-CPC, three specialists in laboratory medicine discussed routine laboratory data of a patient with a ruptured abdominal aortic aneurysm. Then, they and moderators fielded a question-and-answer session with an audience in a hall. It was difficult for us to decide on the correct diagnosis, but we were able to analyze the data logically and reasonably in order to understand the patient's actual condition. It has been revealed that the Department of Laboratory Medicine can support physicians by adding comments to laboratory data that are of practical use to follow a patient.

Concurrent training, a combination of endurance (EE) and resistance exercise (RE) performed in succession, may compromise the muscle hypertrophic adaptations induced by RE alone. However, little is known about the molecular signaling interactions underlying the changes in skeletal muscle adaptation during concurrent training. Here, we used an animal model to investigate whether EE before or after RE affects the molecular signaling associated with muscle protein synthesis, specifically the interaction between RE-induced mammalian target of rapamycin complex 1 (mTORC1) signaling and EE-induced AMP-activated protein kinase (AMPK) signaling. Male Sprague-Dawley rats were divided into five groups: an EE group (treadmill, 25 m/min, 60 min), an RE group (maximum isometric contraction via percutaneous electrical stimulation for 3 × 10 s, 5 sets), an EE before RE group, an EE after RE group, and a nonexercise control group. Phosphorylation of p70S6K, a marker of mTORC1 activity, was significantly increased 3 h after RE in both the EE before RE and EE after RE groups, but the increase was smaller in latter. Furthermore, protein synthesis was greatly increased 6 h after RE in the EE before RE group. Increases in the phosphorylation of AMPK and Raptor were observed only in the EE after RE group. Akt and mTOR phosphorylation were increased in both groups, with no between-group differences. Our results suggest that the last bout of exercise dictates the molecular responses and that mTORC1 signaling induced by any prior bout of RE may be downregulated by a subsequent bout of EE., (Copyright © 2014 the American Physiological Society.)

Pulmonary surfactant, a complex composed primarily of lipids and associated proteins, is synthesized in alveolar type II (ATII) cells and secreted into alveoli to prevent collapse during respiration. Although numerous studies have clarified the fundamental roles of pulmonary surfactant, the molecular mechanisms of transport and secretion of pulmonary surfactant remain totally unknown. Thus, we screened candidate genes by comparing genes with the expressed sequence tag (EST) libraries of embryonic and adult lungs by using the digital differential display method in the National Center for Biotechnology Information (NCBI) database. We identified Sec14-like 3 (Sec14L3) as a new class of lipid-associated proteins highly expressed in ATII cells. We found that Sec14L3 expression is >100-fold increased during the perinatal period in the lung. Furthermore, Sec14L3 bound to small-sized liposomes (30 nm in diameter), but not to large-sized liposomes (100 nm diameter), through its Sec14 domain. Because of the increased curvature, lipid-packing defects are more likely to occur in small-sized liposomes than in large-sized liposomes. Based on these results, we conclude that Sec14L3 is a new class of lipid-packing sensor. Sec14L3 may play important roles in the lung, such as intracellular lipid transport, surfactant maturation, and endo/exocytosis.

A recent study identified ursolic acid (UA) as a potent stimulator of muscle protein anabolism via PI3K/Akt signaling, thereby suggesting that UA can increase Akt-independent mTOR complex 1 (mTORC1) activation induced by resistance exercise via Akt signaling. The purpose of the present study was to investigate the effect of UA on resistance exercise-induced mTORC1 activation. The right gastrocnemius muscle of male Sprague-Dawley rats aged 11 wk was isometrically exercised via percutaneous electrical stimulation (stimulating ten 3-s contractions per set for 5 sets), while the left gastrocnemius muscle served as the control. UA or placebo (PLA; corn oil only) was injected intraperitoneally immediately after exercise. The rats were killed 1 or 6 h after the completion of exercise and the target tissues removed immediately. With placebo injection, the phosphorylation of p70(S6K) at Thr(389) increased 1 h after resistance exercise but attenuated to the control levels 6 h after the exercise. On the other hand, the augmented phosphorylation of p70(S6K) was maintained even 6 h after exercise when UA was injected immediately after exercise. A similar trend of prolonged phosphorylation was observed in PRAS40 Thr(246), whereas UA alone or resistance exercise alone did not alter its phosphorylation level at 6 h after intervention. These results indicate that UA is able to sustain resistance exercise-induced mTORC1 activity.

To compare the effects of a periodic resistance training (PTR) program with those of a continuous resistance training (CTR) program on muscle size and function, 14 young men were randomly divided into a CTR group and a PTR group. Both groups performed high-intensity bench press exercise training [75 % of one repetition maximum (1-RM); 3 sets of 10 reps] for 3 days per week. The CTR group trained continuously over a 24-week period, whereas the PTR group performed three cycles of 6-week training (or retraining), with 3-week detraining periods between training cycles. After an initial 6 weeks of training, increases in cross-sectional area (CSA) of the triceps brachii and pectoralis major muscles and maximum isometric voluntary contraction of the elbow extensors and 1-RM were similar between the two groups. In the CTR group, muscle CSA and strength gradually increased during the initial 6 weeks of training. However, the rate of increase in muscle CSA and 1-RM decreased gradually after that. In the PTR group, increase in muscle CSA and strength during the first 3-week detraining/6-week retraining cycle were similar to that in the CTR group during the corresponding period. However, increase in muscle CSA and strength during the second 3-week detraining/6-week retraining cycle were significantly higher in the PTR group than in the CTR group. Thus, overall improvements in muscle CSA and strength were similar between the groups. The results indicate that 3-week detraining/6-week retraining cycles result in muscle hypertrophy similar to that occurring with continuous resistance training after 24 weeks.

Resistance training-induced muscle anabolism and subsequent hypertrophy occur most rapidly during the early phase of training and become progressively slower over time. Currently, little is known about the intracellular signaling mechanisms underlying changes in the sensitivity of muscles to training stimuli. We investigated the changes in the exercise-induced phosphorylation of hypertrophic signaling proteins during chronic resistance training and subsequent detraining. Male rats were divided into four groups: 1 bout (1B), 12 bouts (12B), 18 bouts (18B), and detraining (DT). In the DT group, rats were subjected to 12 exercise sessions, detrained for 12 days, and then were subjected to 1 exercise session before being killed. Isometric training consisted of maximum isometric contraction, which was produced by percutaneous electrical stimulation of the gastrocnemius muscle every other day. Muscles were removed 24 h after the final exercise session. Levels of total and phosphorylated p70S6K, 4E-BP1, rpS6, and p90RSK levels were measured, and phosphorylation of p70S6K, rpS6, and p90RSK was elevated in the 1B group compared with control muscle (CON) after acute resistance exercise, whereas repeated bouts of exercise suppressed those phosphorylation in both 12B and 18B groups. Interestingly, these phosphorylation levels were restored after 12 days of detraining in the DT group. On the contrary, phosphorylation of 4E-BP1 was not altered with chronic training and detraining, indicating that, with chronic resistance training, anabolic signaling becomes less sensitive to resistance exercise stimuli but is restored after a short detraining period.

We examined the effects of high-intensity resistance training (HIT) and low-intensity blood flow-restricted (LI-BFR) resistance training on carotid arterial compliance. Nineteen young men were randomly divided into HIT (n = 9) or LI-BFR (n = 10) groups. The HIT and LI-BFR groups performed 75 and 30 %, respectively, of one-repetition maximum (1-RM) bench press exercise, 3 days per week for 6 weeks. During the training sessions, the LI-BFR group wore elastic cuffs around the most proximal region of both arms. Muscle cross-sectional area (CSA), 1-RM strength, and carotid arterial compliance were measured before and 3 days after the final training session. Acute changes in systolic arterial pressure (SAP), plasma endothelin-1 (ET-1), nitrite/nitrate (NOx), and noradrenalin concentrations were also measured during and after a bout of training session. The training led to significant increases (P < 0.01) in bench press 1-RM and arm and chest muscle CSA in the two training groups. Carotid arterial compliance decreased significantly (P < 0.05) in the HIT group, but not in the LI-BFR group. There was a significant correlation (r = -0.533, P < 0.05) between the change in carotid arterial compliance and the acute change in SAP during training sessions; however, ET-1 and NOx did not correlate with carotid arterial compliance. Our results suggest that muscle CSA and strength increased following 6 weeks of both HIT and LI-BFR training. However, carotid arterial compliance decreased in only the HIT group, and the changes were correlated with SAP elevations during exercise sessions.

Low-frequency neuromuscular electrical stimulation (NMES) has been used as an endurance exercise model. This study aimed to test whether low-frequency NMES increases the phosphorylation of anabolic signaling molecules and induces skeletal muscle hypertrophy, as seen with high-frequency NMES. Using Sprague-Dawley rats, 1 bout of exercise (with dissection done immediately (Post0) and 3 h (Post3) after exercise) and another 6 sessions of training were performed. All experimental groups consisted of high- and low-frequency stimulation (HFS: 100 Hz; LFS: 10 Hz). Periodic acid-Schiff (PAS) staining was conducted to investigate type II fiber activation, and western blot analysis (WB) was conducted to examine whether NMES leads to anabolic intracellular signaling. At first, we examined the acute effect of exercise. PAS staining revealed that glycogen depletion occurred in both type I and type II fibers. WB results demonstrated that p70S6K phosphorylation was significantly increased by HFS, but there was no significant difference with LFS. In contrast, ERK 1/2 phosphorylation was increased by LFS at Post0. In the 6-session training, the wet weight and myofibrillar protein were significantly increased by both HFS and LFS. In conclusion, LFS has a similar anabolic effect for skeletal muscle hypertrophy as HFS, but the mediating signaling pathway might differ.

The purpose of this study was to investigate the time course of hypertrophic adaptations in both the upper arm and trunk muscles following high-intensity bench press training. Seven previously untrained young men (aged 25 ± 3 years) performed free-weight bench press training 3 days (Monday, Wednesday and Friday) per week for 24 weeks. Training intensity and volume were set at 75% of one repetition maximum (1-RM) and 30 repetitions (3 sets of 10 repetitions, with 2-3 min of rest between sets), respectively. Muscle thickness (MTH) was measured using B-mode ultrasound at three sites: the biceps and triceps brachii and the pectoralis major. Measurements were taken a week prior to the start of training, before the training session on every Monday and 3 days after the final training session. Pairwise comparisons from baseline revealed that pectoralis major MTH significantly increased after week-1 (p = 0.002), triceps MTH increased after week-5 (p = 0.001) and 1-RM strength increased after week-3 (p = 0.001) while no changes were observed in the biceps MTH from baseline. Significant muscle hypertrophy was observed earlier in the chest compared to that of the triceps. Our results indicate that the time course of the muscle hypertrophic response differs between the upper arm and chest.

Several lines of evidence demonstrate the relationship between vitamin E deficiency and cognitive dysfunction in rodent models, but little is known about the underlying mechanisms. In this study, we found axonal injury in the hippocampal CA1 region of vitamin E-deficient and normal old mice using immunohistochemical assay. The number of cells in the hippocampal CA1 region of vitamin E-deficient mice and normal old mice was significantly lower than in normal young mice. It is well known that collapsin response mediator protein (CRMP)-2 plays a crucial role in the maintenance of axonal conditions. The expressions of CRMP-2 in the cerebral cortex and hippocampus of vitamin E-deficient mice were significantly lower than both the regions of normal ones. In normal old mice, the expression of CRMP-2 in the cerebral cortex was significantly lower than in the normal ones. In addition, the appearance of microtubule-associated protein (MAP)-light chain 3 (LC3), a major index of autophagy, was higher in the cerebral cortex and hippocampus of vitamin E-deficient mice than in normal young and old mice. These results indicate that axonal degeneration is induced in living tissues, but not cultured cells, and that changes in CRMP-2 and MAP-LC3 may underlie vitamin E-deficiency-related axonal degeneration.

We investigated the combined effect of low-intensity blood flow restriction and high-intensity resistance training on muscle adaptation. Forty young men (aged 22-32 years) were randomly divided into four groups of ten subjects each: high-intensity resistance training (HI-RT, 75% of one repetition maximum [1-RM]), low-intensity resistance training with blood flow restriction (LI-BFR, 30% 1-RM), combined HI-RT and LI-BFR (CB-RT, twice-weekly LI-BFR and once-weekly HI-RT), and nontraining control (CON). Three training groups performed bench press exercises 3 days/week for 6 weeks. During LI-BFR training sessions, subjects wore pressure cuffs on both arms that were inflated to 100-160 mmHg. Increases in 1-RM were similar in the HI-RT (19.9%) and CB-RT (15.3%) groups and lower in the LI-BFR group (8.7%, p < 0.05). Maximal isometric elbow extension (MVC) increased in the HI-RT (11.3%) and CB-RT (6.6%) groups; there was no change in the LI-BFR group (-0.2%). The cross-sectional area (CSA) of the triceps brachii (TB) increased (p < 0.05) in the HI-RT (8.6%), CB-RT (7.2%), and LI-BFR (4.4%) groups. The change in relative isometric strength (MVC divided by TB CSA) was greater (p < 0.05) in the HI-RT group (3.3%) than in the LI-BFR (-3.5%) and CON (-0.1%) groups. Following training, relative dynamic strength (1-RM divided by TB CSA) was increased (p < 0.05) by 10.5% in the HI-RT group and 6.7% in the CB-RT group. None of the variables in the CON group changed. Our results show that low-intensity resistance training with BFR-induced functional muscle adaptations is improved by combining it with HI-RT.

We examined the relationship between training-induced limb and trunk muscle hypertrophy in high-intensity resistance training (HIT) or blood flow-restricted low-intensity resistance training (LI-BFR) programmes. Thirty young men were divided into three groups: HIT (n = 10), LI-BFR (n = 10) and non-training control (CON, n = 10). The HIT and LI-BFR groups performed 75% and 30%, respectively, of one-repetition maximal (1-RM) bench press exercise, 3 days per week for 6 weeks. During the training sessions, the LI-BFR group wore elastic cuffs around the most proximal region of both arms. Muscle cross-sectional area (CSA) and 1-RM bench press strength were measured before and 3 days after the final training session. Total training volumes (lifting weight × number of repetitions) for all of the sessions were similar between the two training groups. The training led to a significant increase (P < 0·05) in bench press 1-RM in the two training groups, but not in the CON group. Triceps brachii and pectoralis major muscle CSA increased 8·8% and 15·8% (P < 0·01), respectively, in the HIT group and 4·9% (P < 0·05) and 8·3% (P < 0·01), respectively, in the LI-BFR group, but not in the CON group (-1·1% and 0·0%, respectively). There was significant correlation (r = 0·70, P < 0·05) between increases in triceps brachii and pectoralis major muscle CSA in the HIT group; however, the correlation was lower and non-significant in the LI-BFR group (r = 0·54). Our results suggest that limb and trunk muscle hypertrophy occurs simultaneously during HIT but not during LI-BFR, possibly owing to individual differences in activation of the arm and chest muscles during the training sessions., (© 2011 The Authors. Clinical Physiology and Functional Imaging © 2011 Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

To determine muscle adaptations to retraining after short-term detraining, we examined the effects of continuous and interrupted resistance training on muscle size and strength in previously untrained men. Fifteen young men were divided into continuous training (CTr) or retraining (RTr) groups and performed high-intensity bench press training. The CTr group trained continuously for 15 weeks, while the RTr group trained for 6 weeks, stopped for a 3-week detraining period and resumed training at week 10. After the initial training phase, increases (P<0·01) in one repetition maximum (1-RM) and magnetic resonance imaging-measured triceps brachii and pectorals major muscle cross-sectional areas (CSAs) were similar in both groups. Muscle CSA and 1-RM increased (P<0·05) continuously for the CTr group, but the muscle adaptations were lower (P<0·05) after the last 6-week training period than after the initial phase. In the RTr group, there were no significant decreases in muscle CSA and 1-RM after the 3-week detraining period, and increases in muscle CSA after retraining were similar to those observed after initial training. Ultimately, improvements in 1-RM and muscle CSA in both groups were similar after the 15-week training period. Our results suggest that compared with continuous 15-week training, 3-week detraining does not inhibit muscle adaptations., (© 2011 The Authors. Clinical Physiology and Functional Imaging © 2011 Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

We examined the effects of walk training combined with leg blood flow reduction (BFR) on muscle hypertrophy as well as on peak oxygen uptake (VO₂ peak) in older individuals. Both the BFR walk training (BFR-Walk, n = 10, age; 64 ± 1 years, body mass index [BMI]; 22.5 ± 0.9 kg/m²) and control walk training (CON-Walk, n = 8, age; 68 ± 1 years, BMI; 23.2 ± 1.0 kg/m²) groups performed 20 minutes of treadmill walking at an exercise intensity of 45% of heart rate reserve, 4 days per week, for 10 weeks. The BFR-Walk group wore pressure belts (160-200 mm Hg) on both legs during training. After the training, magnetic resonance imaging-measured thigh muscle cross-sectional area (3.1%, p < .01) and muscle volume (3.7%, p < .01) as well as maximal isometric (5.9%, p < .05) and isokinetic (up to 22%, p < .01) strength increased in the BFR-Walk group, but not in the CON-Walk group. Estimated VO₂ peak during a bicycle graded exercise test increased (p < .05) and correlated with oxygen pulse in both groups. In conclusion, BFR walk training improves both muscle volume and strength in older women.

Hepatitis C virus (HCV) is one of the viruses known to cause hepatic cancer. HCV is also believed to be involved in malignant lymphoma. In this paper, we investigated characteristics of malignant lymphoma cases that were anti-HCV antibody (HCV-Ab) positive. We were able to perform pathological examinations on 13 out of 14 HCV-positive cases. Of these, lymphoid tissues of 10 stained positive for HCV-Ab. There was no significant correlation between the degree of HCV staining and the rate of recurrence or resistance to treatment. However, there did appear to be a consistent decrease in the amount of HCV-RNA between pre- and posttreatment among HCV-Ab-positive cases; that is, treatment-resistant cases that exhibited resistance from the first treatment and recurrent cases more frequently had a higher HCV level at treatment termination compared to the pretreatment level. This suggests that the HCV virus either accelerates oncogenesis by direct interaction with B cells or indirectly affects lymphoma prognosis.

Single-joint resistance training with blood flow restriction (BFR) results in significant increases in arm or leg muscle size and single-joint strength. However, the effect of multijoint BFR training on both blood flow restricted limb and non-restricted trunk muscles remain poorly understood. To examine the impact of BFR bench press training on hypertrophic response to non-restricted (chest) and restricted (upper-arm) muscles and multi-joint strength, 10 young men were randomly divided into either BFR training (BFR-T) or non-BFR training (CON-T) groups. They performed 30% of one repetition maximal (1-RM) bench press exercise (four sets, total 75 reps) twice daily, 6 days week(-1) for 2 weeks. During the exercise session, subjects in the BFR-T group placed elastic cuffs proximally on both arms, with incremental increases in external compression starting at 100 mmHg and ending at 160 mmHg. Before and after the training, triceps brachii and pectoralis major muscle thickness (MTH), bench press 1-RM and serum anabolic hormones were measured. Two weeks of training led to a significant increase (P<0.05) in 1-RM bench press strength in BFR-T (6%) but not in CON-T (-2%). Triceps and pectoralis major MTH increased 8% and 16% (P<0.01), respectively, in BFR-T, but not in CON-T (-1% and 2%, respectively). There were no changes in baseline concentrations of anabolic hormones in either group. These results suggest that BFR bench press training leads to significant increases in muscle size for upper arm and chest muscles and 1-RM strength.

Concurrent improvements in aerobic capacity and muscle hypertrophy in response to a single mode of training have not been reported. We examined the effects of low-intensity cycle exercise training with and without blood flow restriction (BFR) on muscle size and maximum oxygen uptake (VO2max). A group of 19 young men (mean age ± SD: 23.0 ± 1.7 years) were allocated randomly into either a BFR-training group (n=9, BFR-training) or a non-BFR control training group (n=10, CON-training), both of which trained 3 days/wk for 8 wk. Training intensity and duration were 40% of VO2max and 15 min for the BFR-training group and 40% of VO2max and 45 min for the CON-training group. MRI-measured thigh and quadriceps muscle cross-sectional area and muscle volume increased by 3.4-5.1% (P < 0.01) and isometric knee extension strength tended to increase by 7.7% (p < 0.10) in the BFR-training group. There was no change in muscle size (~0.6%) and strength (~1.4%) in the CON-training group. Significant improvements in VO2max (6.4%) and exercise time until exhaustion (15.4%) were observed in the BFR-training group (p < 0.05) but not in the CON-training group (-0.1 and 3. 9%, respectively). The results suggest that low-intensity, short-duration cycling exercise combined with BFR improves both muscle hypertrophy and aerobic capacity concurrently in young men. Key pointsConcurrent improvements in aerobic capacity and muscle hypertrophy in response to a single mode of training have not been reported.In the present study, low-intensity (40% of VO2max) cycle training with BFR can elicit concurrent improvement in muscle hypertrophy and aerobic capacity.

Rituximab is a drug used for the treatment of B-cell non-Hodgkin's lymphoma, and its range of use has expanded to the treatment of collagen diseases such as idiopathic thrombocytopenic purpura and rheumatoid arthritis. One serious complication of rituximab use is the reactivation of dormant hepatitis B virus, and prevention of this phenomenon has become an urgent issue. This paper provides a general outline of the problem through an analysis of patient cases that we and other groups have experienced to date.

Pulmonary surfactant is synthesized and secreted by pulmonary alveolar type II epithelial cells (type II cells). It passes through the alveolar lining fluid and adsorbs to the air-liquid interface. The process from secretion to adsorption is not yet entirely understood. To acquire a detailed understanding of this process, we used multiple observations of type II cells isolated from rat lungs under electron microscopy (EM) and confocal laser scanning microscopy (CLSM). Transmission EM observation demonstrated a loosening process of the intracellular lamellar bodies from the inside to the outside of the cell. Scanning EM observation revealed bubble-like protrusions from the cell surface, and differential interference contrast microscopy illustrated the protrusions expanding with time. CLSM observation with FM 1-43, a fluorescent membrane probe, revealed that the bubble-like protrusions were composed of phospholipids. Thus, we have demonstrated that isolated rat type II cells protrude intracellular lamellar bodies by forming bubble-like structures, possibly enabling them to adsorb to the air-liquid interface directly. These observations suggest a new mechanism for surfactant secretion from type II cells.

Three novel furoquinoline alkaloid oxogeranyl ethers (1-3) and one known furoquinoline alkaloid (4) were isolated from the leaves of Boninia glabra, an endemic plant of the Bonin Islands. Their structures were elucidated on the basis of spectroscopic analysis.

Platelet-activating factor (PAF) is a potent lipid mediator playing various inflammatory and physiological roles. PAF is biosynthesized through two independent pathways called the de novo and remodeling pathways. Lyso-PAF acetyltransferase (lyso-PAF AT) was believed to biosynthesize PAF under inflammatory conditions, through the remodeling pathway. The first isolated lyso-PAF AT (LysoPAFAT/LPCAT2) had consistent properties. However, we show in this study the finding of a second lyso-PAF AT working under noninflammatory conditions. We partially purified a Ca(2+)-independent lyso-PAF AT from mouse lung. Immunoreactivity for lysophosphatidylcholine acyltransferase 1 (LPCAT1) was detected in the active fraction. Lpcat1-transfected Chinese hamster ovary cells exhibited both LPCAT and lyso-PAF AT activities. We confirmed that LPCAT1 transfers acetate from acetyl-CoA to lyso-PAF by the identification of an acetyl-CoA (and other acyl-CoAs) interacting site in LPCAT1. We further showed that LPCAT1 activity and expression are independent of inflammatory signals. Therefore, these results suggest the molecular diversity of lyso-PAF ATs is as follows: one (LysoPAFAT/LPCAT2) is inducible and activated by inflammatory stimulation, and the other (LPCAT1) is constitutively expressed. Each lyso-PAF AT biosynthesizes inflammatory and physiological amounts of PAF, depending on the cell type. These findings provide important knowledge for the understanding of the diverse pathological and physiological roles of PAF.

Phosphatidylcholine (1,2-diacyl-sn-glycero-3-phosphocholine, PC), is an important constituent of biological membranes. It is also the major component of serum lipoproteins and pulmonary surfactant. In the remodeling pathway of PC biosynthesis, 1-acyl-sn-glycero-3-phosphocholine (LPC) is converted to PC by acyl-CoA:lysophosphatidylcholine acyltransferase (LPCAT, EC 2.3.1.23). Whereas LPCAT activity has been detected in several tissues, the structure and detailed biochemical information on the enzyme have not yet been reported. Here, we present the cloning and characterization of a cDNA for mouse lung-type LPCAT (LPCAT1). The cDNA encodes an enzyme of 60 kDa, with three putative transmembrane domains. When expressed in Chinese hamster ovary cells, mouse LPCAT1 exhibited Ca(2+)-independent activity with a pH optimum between 7.4 and 10. LPCAT1 demonstrated a clear preference for saturated fatty acyl-CoAs, and 1-myristoyl- or 1-palmitoyl-LPC as acyl donors and acceptors, respectively. Furthermore, the enzyme was predominantly expressed in the lung, in particular in alveolar type II cells. Thus, the enzyme might synthesize phosphatidylcholine in pulmonary surfactant and play a pivotal role in respiratory physiology.

The prompt gamma-ray emission from gamma-ray bursts (GRBs) should be detectable out to distances of z > 10 (ref. 1), and should therefore provide an excellent probe of the evolution of cosmic star formation, reionization of the intergalactic medium, and the metal enrichment history of the Universe. Hitherto, the highest measured redshift for a GRB has been z = 4.50 (ref. 5). Here we report the optical spectrum of the afterglow of GRB 050904 obtained 3.4 days after the burst; the spectrum shows a clear continuum at the long-wavelength end of the spectrum with a sharp cut-off at around 9,000 A due to Lyman alpha absorption at z approximately 6.3 (with a damping wing). A system of absorption lines of heavy elements at z = 6.295 +/- 0.002 was also detected, yielding the precise measurement of the redshift. The Si ii fine-structure lines suggest a dense, metal-enriched environment around the progenitor of the GRB.

We investigated the incidence and the varieties of arrhythmia during exercise training in patients who underwent cardiac surgery. Subjects were 1293 patients who underwent cardiac surgery and enrolled our cardiac rehabilitation program. According to the charts and cardiac rehabilitation records, we evaluated the incidence and the varieties of arrhythmia provoked by exercise training in patients after cardiac surgery retrospectively. The arrhythmias related to the exercise training were provoked in 12 times, and the incidence was only 0.09% (12/13646). Atrial fibrillation was the most common arrhythmia, and the incidence was 41.6% (5/12) in these patients. Moreover, these arrhythmias occurred within 2 weeks after surgery. Although most patients recovered to the sinus rhythm spontaneously, 3 patients needed medical treatment or cardioversion. We concluded that the arrhythmia provoked by exercise training in patients after cardiac surgery were rare, non-fatal, and common in the early recovery phase after surgery. However, the supervised exercise training was required in those patients, particularly in early recovery phase of cardiac surgery.

The Yamato-791198 and Murchison carbonaceous chondrites were analyzed for dipeptides and diketopiperazines as well as amino acids and hydantoins by gas chromatography combined with mass spectrometry. Glycylglycine (gly-gly) and cyclo(gly-gly) were detected at the concentrations of 11 and 18 pmol g-1, respectively, in Yamato-791198, and 4 and 23 pmol g-1, respectively, in Murchison. No other dipeptide and diketopiperazine were detected. Five hydantoins were detected at 8 to 65 pmol g-1 in Yamato-791198 and seven in Murchison at 6 to 104 pmol g-1. Total concentration of the glycine (gly) dimers is approximately four orders of magnitude less than the concentration of free gly in Yamato-791198, and three orders of magnitude less than that in Murchison. The absence of L- and LL-stereoisomers of dipeptides consisting of protein amino acids indicates that gly-gly and cyclo(gly-gly) detected are native to the chondries and not from terrestrial contaminants. A possibility was discussed that the gly dimers might have been formed by condensation of gly monomers but not formed through N-carboxyanhydrides of gly.

A 55-year-old male patient underwent CABG for triple-vessel disease using the minimal access approach. The procedure was performed through a limited (10 cm) left para-sternal thoracotomy using extracorporeal circulation established with a usual aortic cannula, and pulmonary arterial and right atrial drainage. The myocardium was protected by antegrade administration of cold cardioplegic solution while the aorta was being cross-clampled. The saphenous vein graft was connected sequentially to the 4 PD and OM branches, and the left internal thoracic artery was grafted to the LAD. The postoperative course was uneventful and coronary angiography showed that all three grafts were patent. The patient was discharged one week postoperatively.