DISC1 and reelin interact to alter cognition, inhibition, and neurogenesis in a novel mouse model of schizophrenia.

The etiology of schizophrenia (SCZ) is multifactorial, and depending on a host of genetic and environmental factors. Two putative SCZ susceptibility genes, Disrupted-in-Schizophrenia-1 (DISC1) and reelin (RELN), interact at a molecular level, suggesting that combined disruption of both may lead to an intensified SCZ phenotype. To examine this gene-gene interaction, we produced a double mutant mouse line.

Circadian rhythm shifts and alcohol access in adolescence synergistically increase alcohol preference and intake in adulthood in male C57BL/6 mice.

Background: Adolescents have a natural tendency to be night owls, maintaining delayed circadian rhythms, and this rhythm is in direct conflict with the early wake times required during the school year. This leads to 'social jetlag', chronic circadian stress or desynchrony (CD) in which the rhythm of the intrinsic body clock is out of sync with behavior. CD increases alcohol intake in adolescents and adults, yet it is unknown whether adolescent CD also increases long-term addiction risk.

Robo4 is constitutively shed by ADAMs from endothelial cells and the shed Robo4 functions to inhibit Slit3-induced angiogenesis.

Roundabout 4 (Robo4) is a transmembrane receptor that expresses specifically in endothelial cells. Soluble Robo4 was reported in the human plasma and mouse serum and is inhibitory towards FGF- and VEGF-induced angiogenesis. It remains unknown how soluble Robo4 is generated and if soluble Robo4 regulates additional angiogenic signaling.

Application of a Mutant Cell Library to Determine the Structure-Function Relationship of Heparan Sulfate in Facilitating FGF2-FGFR1 Signaling.

Heparan sulfate (HS) is a linear polysaccharide with complex structures and modulates a wide range of biological functions. Elucidating the structure-function relationship of HS has been challenging. Recently, we generated a HS mutant mouse lung endothelial cell library by systematic deletion of HS genes expressed in the cell individually or in their combination.

Inhibition of casein kinase 1 δ/ε improves cognitive performance in adult C57BL/6J mice.

Time-of-day effects have been noted in a wide variety of cognitive behavioral tests, and perturbation of the circadian system, either at the level of the master clock in the SCN or downstream, impairs hippocampus-dependent learning and memory. A number of kinases, including the serine-threonine casein kinase 1 (CK1) isoforms CK1δ/ε, regulate the timing of the circadian period through post-translational modification of clock proteins. Modulation of these circadian kinases presents a novel treatment direction for cognitive deficits through circadian modulation.

Wake-sleep cycles are severely disrupted by diseases affecting cytoplasmic homeostasis.

The circadian clock is based on a transcriptional feedback loop with an essential time delay before feedback inhibition. Previous work has shown that PERIOD (PER) proteins generate circadian time cues through rhythmic nuclear accumulation of the inhibitor complex and subsequent interaction with the activator complex in the feedback loop. Although this temporal manifestation of the feedback inhibition is the direct consequence of PER's cytoplasmic trafficking before nuclear entry, how this spatial regulation of the pacemaker affects circadian timing has been largely unexplored.

Accelerated sarcopenia in Cu/Zn superoxide dismutase knockout mice.

Mice lacking Cu/Zn-superoxide dismutase (Sod1 or Sod1KO mice) show high levels of oxidative stress/damage and a 30% decrease in lifespan. The Sod1KO mice also show many phenotypes of accelerated aging with the loss of muscle mass and function being one of the most prominent aging phenotypes. Using various genetic models targeting the expression of Cu/Zn-superoxide dismutase to specific tissues, we evaluated the role of motor neurons and skeletal muscle in the accelerated loss of muscle mass and function in Sod1KO mice.

Haploinsufficiency of myostatin protects against aging-related declines in muscle function and enhances the longevity of mice.

The molecular mechanisms behind aging-related declines in muscle function are not well understood, but the growth factor myostatin (MSTN) appears to play an important role in this process. Additionally, epidemiological studies have identified a positive correlation between skeletal muscle mass and longevity. Given the role of myostatin in regulating muscle size, and the correlation between muscle mass and longevity, we tested the hypotheses that the deficiency of myostatin would protect oldest-old mice (28-30 months old) from an aging-related loss in muscle size and contractility, and would extend the maximum lifespan of mice.

Mouse forepaw lumbrical muscles are resistant to age-related declines in force production.

A progressive loss of skeletal muscle mass and force generating capacity occurs with aging. Mice are commonly used in the study of aging-associated changes in muscle size and strength, with most models of aging demonstrating 15-35% reductions in muscle mass, cross-sectional area (CSA), maximum isometric force production (Po) and specific force (sPo), which is Po/CSA. The lumbrical muscle of the mouse forepaw is exceptionally small, with corresponding short diffusion distances that make it ideal for in vitro pharmacological studies and measurements of contractile properties.

Motor unit changes seen with skeletal muscle sarcopenia in oldest old rats.

Sarcopenia leads to many changes in skeletal muscle that contribute to atrophy, force deficits, and subsequent frailty. The purpose of this study was to characterize motor unit remodeling related to sarcopenia seen in extreme old age. Whole extensor digitorum longus muscle and motor unit contractile properties were measured in 19 adult (11-13 months) and 12 oldest old (36-37 months) Brown-Norway rats.

Weakness of whole muscles in mice deficient in Cu, Zn superoxide dismutase is not explained by defects at the level of the contractile apparatus.

Mice deficient in Cu,Zn superoxide dismutase (Sod1 (-/-) mice) demonstrate elevated oxidative stress associated with rapid age-related declines in muscle mass and force. The decline in mass for muscles of Sod1 (-/-) mice is explained by a loss of muscle fibers, but the mechanism underlying the weakness is not clear. We hypothesized that the reduced maximum isometric force (F o) normalized by cross-sectional area (specific F o) for whole muscles of Sod1 (-/-) compared with wild-type (WT) mice is due to decreased specific F o of individual fibers.

Effects of high- and low-velocity resistance training on the contractile properties of skeletal muscle fibers from young and older humans.

A two-arm, prospective, randomized, controlled trial study was conducted to investigate the effects of movement velocity during progressive resistance training (PRT) on the size and contractile properties of individual fibers from human vastus lateralis muscles. The effects of age and sex were examined by a design that included 63 subjects organized into four groups: young (20-30 yr) men and women, and older (65-80 yr) men and women. In each group, one-half of the subjects underwent a traditional PRT protocol that involved shortening contractions at low velocities against high loads, while the other half performed a modified PRT protocol that involved contractions at 3.

Non-uniform distribution of strain during stretch of relaxed skeletal muscle fibers from rat soleus muscle.

Tension and regional average sarcomere length (L(s)) behavior were examined during repeated stretches of single, permeabilized, relaxed muscle fibers isolated from the soleus muscles of rats. We tested the hypothesis that during stretches of single permeabilized fibers, the global fiber strain is distributed non-uniformly along the length of a relaxed fiber in a repeatable pattern. Each fiber was subjected to eight constant-velocity stretch and release cycles with a strain of 32% and strain rate of 54% s(-1).

Lateral transmission of force is impaired in skeletal muscles of dystrophic mice and very old rats.

The dystrophin–glycoprotein complex (DGC) provides an essential link from the muscle fibre cytoskeleton to the extracellular matrix. In dystrophic humans and mdx mice, mutations in the dystrophin gene disrupt the structure of the DGC causing severe damage to muscle fibres. In frog muscles, transmission of force laterally from an activated fibre to the muscle surface occurs without attenuation, but lateral transmission of force has not been demonstrated in mammalian muscles.

Genetic ablation of complement C3 attenuates muscle pathology in dysferlin-deficient mice.

Mutations in the dysferlin gene underlie a group of autosomal recessive muscle-wasting disorders denoted as dysferlinopathies. Dysferlin has been shown to play roles in muscle membrane repair and muscle regeneration, both of which require vesicle-membrane fusion. However, the mechanism by which muscle becomes dystrophic in these disorders remains poorly understood.

Reactive oxygen species on bone mineral density and mechanics in Cu,Zn superoxide dismutase (Sod1) knockout mice.

Reactive oxygen species (ROS) play a role in a number of degenerative conditions including osteoporosis. Mice deficient in Cu,Zn-superoxide dismutase (Sod1) (Sod1(-/-) mice) have elevated oxidative stress and decreased muscle mass and strength compared to wild-type mice (WT) and appear to have an accelerated muscular aging phenotype. Thus, Sod1(-/-) mice may be a good model for evaluating the effects of free radical generation on diseases associated with aging.

Soleus muscle in glycosylation-deficient muscular dystrophy is protected from contraction-induced injury.

The glycosylation of dystroglycan is required for its function as a high-affinity laminin receptor, and loss of dystroglycan glycosylation results in congenital muscular dystrophy. The purpose of this study was to investigate the functional defects in slow- and fast-twitch muscles of glycosylation-deficient Large(myd) mice. While a partial alteration in glycosylation of dystroglycan in heterozygous Large(myd/+) mice was not sufficient to alter muscle function, homozygous Large(myd/myd) mice demonstrated a marked reduction in specific force in both soleus and extensor digitorum longus (EDL) muscles.

Characterization of skeletal muscle effects associated with daptomycin in rats.

Daptomycin is a lipopeptide antibiotic with strong bactericidal effects against Gram-positive bacteria and minor side effects on skeletal muscles. The type and magnitude of the early effect of daptomycin on skeletal muscles of rats was quantified by histopathology, examination of contractile properties, Evans Blue Dye uptake, and effect on the patch repair process. A single dose of daptomycin of up to 200 mg/kg had no effect on muscle fibers.

Effect of daptomycin on primary rat muscle cell cultures in vitro.

Daptomycin is a lipopeptide antibiotic that has strong bactericidal activity against Gram-positive bacteria and that was previously reported to exhibit minor side effects on skeletal muscle. This study was designed to further characterize the effect of daptomycin on skeletal muscle through the use of primary cultures of muscles from rats. Our investigations demonstrated that daptomycin has a concentration-dependent and time-dependent effect on the plasma membrane of primary cultures of differentiated, spontaneously contracting rat myotubes.

Basal lamina strengthens cell membrane integrity via the laminin G domain-binding motif of alpha-dystroglycan.

Skeletal muscle basal lamina is linked to the sarcolemma through transmembrane receptors, including integrins and dystroglycan. The function of dystroglycan relies critically on posttranslational glycosylation, a common target shared by a genetically heterogeneous group of muscular dystrophies characterized by alpha-dystroglycan hypoglycosylation. Here we show that both dystroglycan and integrin alpha7 contribute to force-production of muscles, but that only disruption of dystroglycan causes detachment of the basal lamina from the sarcolemma and renders muscle prone to contraction-induced injury.

The aging of elite male athletes: age-related changes in performance and skeletal muscle structure and function.

Objective: The paper addresses the degree to which the attainment of the status as an elite athlete in different sports ameliorates the known age-related losses in skeletal muscle structure and function.

Design: The retrospective design, based on comparisons of published data on former elite and masters athletes and data on control subjects, assessed the degree to which the attainment of elite and masters athlete status ameliorated the known age-related changes in skeletal muscle structure and function.

Setting: Institutional.

Sarcolemma-localized nNOS is required to maintain activity after mild exercise.

Many neuromuscular conditions are characterized by an exaggerated exercise-induced fatigue response that is disproportionate to activity level. This fatigue is not necessarily correlated with greater central or peripheral fatigue in patients, and some patients experience severe fatigue without any demonstrable somatic disease. Except in myopathies that are due to specific metabolic defects, the mechanism underlying this type of fatigue remains unknown.

Koshikamide B, a cytotoxic peptide lactone from a marine sponge Theonella sp.

Koshikamide B (1) has been isolated from two separate collections of the marine sponge Theonella sp. as the major cytotoxic constituent. Koshikamide B is a 17-residue peptide lactone composed of six proteinogenic amino acids, two D-isomers of proteinogenic amino acids, seven N-methylated amino acids, and two unusual amino acid residues.

Force deficits and breakage rates after single lengthening contractions of single fast fibers from unconditioned and conditioned muscles of young and old rats.

The deficit in force generation is a measure of the magnitude of damage to sarcomeres caused by lengthening contractions of either single fibers or whole muscles. In addition, permeabilized single fibers may suffer breakages. Our goal was to understand the interaction between breakages and force deficits in "young" and "old" permeabilized single fibers from control muscles of young and old rats and "conditioned" fibers from muscles that completed a 6-wk program of in vivo lengthening contractions.