Hyperammonemia results in reduced muscle function independent of muscle mass.

The mechanism of the nearly universal decreased muscle strength in cirrhosis is not known. We evaluated whether hyperammonemia in cirrhosis causes contractile dysfunction independent of reduced skeletal muscle mass. Maximum grip strength and muscle fatigue response were determined in cirrhotic patients and controls.

Alterations in lung gene expression in streptozotocin-induced diabetic rats.

Background: Diabetes profoundly affects gene expression in organs such as heart, skeletal muscle, kidney and liver, with areas of perturbation including carbohydrate and lipid metabolism, oxidative stress, and protein ubiquitination. Type 1 diabetes impairs lung function, but whether gene expression alterations in the lung parallel those of other tissue types is largely unexplored.

Methods: Lung from a rat model of diabetes mellitus induced by streptozotocin was subjected to gene expression microarray analysis.

Gene expression of sternohyoid and diaphragm muscles in type 2 diabetic rats.

Background: Type 2 diabetes differs from type 1 diabetes in its pathogenesis. Type 1 diabetic diaphragm has altered gene expression which includes lipid and carbohydrate metabolism, ubiquitination and oxidoreductase activity. The objectives of the present study were to assess respiratory muscle gene expression changes in type 2 diabetes and to determine whether they are greater for the diaphragm than an upper airway muscle.

The Effects of K(+) Channel Blockade on Eccentric and Isotonic Twitch and Fatiguing Contractions in situ.

K(+) channel blockers like 3,4-diaminopyridine (DAP) can double isometric muscle force. Functional movements require more complex concentric and eccentric contractions, however the effects of K(+) channel blockade on these types of contractions in situ are unknown. Extensor digitorum longus (EDL) muscles were stimulated in situ with and without DAP in anesthetized rats and fatigability was addressed using a series of either concentric or eccentric contractions.

Impaired Wheel Running Exercise in CLC-1 Chloride Channel-Deficient Myotonic Mice.

Background: Genetic deficiency of the muscle CLC-1 chloride channel leads to myotonia, which is manifested most prominently by slowing of muscle relaxation. Humans experience this as muscle stiffness upon initiation of contraction, although this can be overcome with repeated efforts (the "warm-up" phenomenon). The extent to which CLC-1 deficiency impairs exercise activity is controversial.

Expression of a dominant negative CELF protein in vivo leads to altered muscle organization, fiber size, and subtype.

Background: CUG-BP and ETR-3-like factor (CELF) proteins regulate tissue- and developmental stage-specific alternative splicing in striated muscle. We previously demonstrated that heart muscle-specific expression of a nuclear dominant negative CELF protein in transgenic mice (MHC-CELFΔ) effectively disrupts endogenous CELF activity in the heart in vivo, resulting in impaired cardiac function. In this study, transgenic mice that express the dominant negative protein under a skeletal muscle-specific promoter (Myo-CELFΔ) were generated to investigate the role of CELF-mediated alternative splicing programs in normal skeletal muscle.

Differential susceptibility of muscles to myotonia and force impairment in a mouse model of myotonic dystrophy.

Introduction: Myotonic dystrophy, or dystrophia myotonica (DM), is characterized by prominent muscle wasting and weakness as well as delayed muscle relaxation resulting from persistent electrical discharges.

Methods: We hypothesized heterogeneity among muscles in degree of weakness and myotonia in an expanded [(CUG)(250)] repeats transgenic (HSA(LR)) mouse DM model. Muscle contraction was compared among diaphragm, extensor digitorum longus (EDL), and soleus muscles.

Fatigue-inducing stimulation resolves myotonia in a drug-induced model.

Background: Slowed muscle relaxation is the contractile hallmark of myotonia congenita, a disease caused by genetic CLC-1 chloride channel deficiency, which improves with antecedent brief contractions ("warm-up phenomenon"). It is unclear to what extent the myotonia continues to dissipate during continued repetitive contractions and how this relates temporally to muscle fatigue. Diaphragm, EDL, and soleus muscles were examined in vitro during repetitive 20 Hz and 50 Hz train stimulation in a drug-induced (9-AC) rat myotonia model.

Differential expression of lipid and carbohydrate metabolism genes in upper airway versus diaphragm muscle.

Study Objectives: Contractile properties of upper airway muscles influence upper airway patency, an issue of particular importance for subjects with obstructive sleep apnea. Expression of genes related to cellular energetics is, in turn, critical for the maintenance of contractile integrity over time during repetitive activation. We tested the hypothesis that sternohyoid has lower expression of genes related to lipid and carbohydrate energetic pathways than the diaphragm.

Improvement of diaphragm and limb muscle isotonic contractile performance by K+ channel blockade.

The K+ channel blocking aminopyridines greatly improve skeletal muscle isometric contractile performance during low to intermediate stimulation frequencies, making them potentially useful as inotropic agents for functional neuromuscular stimulation applications. Most restorative applications involve muscle shortening; however, previous studies on the effects of aminopyridines have involved muscle being held at constant length. Isotonic contractions differ substantially from isometric contractions at a cellular level with regards to factors such as cross-bridge formation and energetic requirements.

Gene expression profiling in the type 1 diabetes rat diaphragm.

Background: Respiratory muscle contractile performance is impaired by diabetes, mechanisms of which included altered carbohydrate and lipid metabolism, oxidative stress and changes in membrane electrophysiology. The present study examined to what extent these cellular perturbations involve changes in gene expression.

Methodology/principal Findings: Diaphragm muscle from streptozotocin-diabetic rats was analyzed with Affymetrix gene expression arrays.

Long-lasting in vivo inotropic effects of the K(+) channel blocker 3,4-diaminopyridine during fatigue-inducing stimulation.

Blocking K(+) channels with aminopyridines enhances muscle contractile performance in vitro, but the improvements are relatively short-lasting during fatigue-inducing stimulation. We hypothesized that in vivo inotropic actions persist over long periods of fatigue-inducing stimulation. The effects of 3,4-diaminopyridine (DAP) were evaluated for rat extensor digitorum longus (EDL) muscle.

Contrast between cardiac left ventricle and diaphragm muscle in expression of genes involved in carbohydrate and lipid metabolism.

The heart and diaphragm both need appropriate metabolic machinery to ensure long-term energy supplies, as they must contract rhythmically without cessation for the entire lifetime of the organism to ensure homeostasis of oxygen and carbon dioxide exchange. However, their energy requirements differ due to disparities in mechanical loads. Understanding how these two muscles converge and diverge in their approaches to meeting their metabolic demands may suggest novel strategies for improving cardiac and skeletal muscle long-term performance in health and disease.

Inotropic effects of the K+ channel blocker 3,4-diaminopyridine on fatigued diaphragm muscle.

K(+) channels play important roles in skeletal muscle contraction by regulating action potential duration. Blocking these channels, for example with 3,4-diaminopyridine (DAP), augments muscle force considerably, and these force increases are maintained well during fatigue-inducing contractions. The present study tested the hypothesis that K(+) channel blockade also improves force of previously fatigued muscle.

Isotonic fatigue in laminin alpha2-deficient dy/dy dystrophic mouse diaphragm.

Laminin alpha2 deficiency causes approximately 50% of human congenital muscular dystrophies. Muscle in the corresponding dy/dy mouse model has reduced force but increased fatigue resistance during isometric contractions. To determine whether a similar pattern of alterations is present during isotonic contractions, dy/dy diaphragm was studied in vitro.

Oxidoreductase, morphogenesis, extracellular matrix, and calcium ion-binding gene expression in streptozotocin-induced diabetic rat heart.

Diabetes has far-ranging effects on cardiac structure and function. Previous gene expression studies of the heart in animal models of type 1 diabetes concur that there is altered expression of genes involved in lipid and protein metabolism, but they diverge with regard to expression changes involving many other functional groups of genes of mechanistic importance in diabetes-induced cardiac dysfunction. To obtain additional information about these controversial areas, genome-wide expression was assessed using microarrays in left ventricle from streptozotocin-diabetic and normal rats.

Isotonic contractile impairment due to genetic CLC-1 chloride channel deficiency in myotonic mouse diaphragm muscle.

The hallmark of genetic CLC-1 chloride channel deficiency in myotonic humans, goats and mice is delayed muscle relaxation resulting from persistent electrical discharges. In addition to the ion channel defect, muscles from myotonic humans and mice also have major changes in fibre type and myosin isoform composition, but the extent to which this affects isometric contractions remains controversial. Many muscles, including the diaphragm, shorten considerably during normal activities, but shortening contractions have never been assessed in myotonic muscle.

Inotropic effects of the K+ channel blocker 3,4-diaminopyridine: differential responses of rat soleus and extensor digitorum longus.

The K+ channel blocker 3,4-diaminopyrindine (DAP) increases diaphragm force, use of which could potentially improve muscle performance during functional neuromuscular stimulation. To determine the extent of hindlimb muscle force augmentation, and delineate whether DAP effects vary in muscles comprised of mainly slow versus fast fibers, rat soleus, extensor digitorum longus (EDL) and diaphragm muscle samples were studied in vitro. DAP increased force of all three muscles, but at high concentrations the force increases were transient and were followed by declines in force below baseline.

Gene expression microarrays and respiratory muscles.

The routine measurement of the expression of tens of thousands of gene transcripts, simultaneously, is a defining advance of the last decade which has been made possible by microarray technology. Using this very powerful approach, a pattern has emerged from a number of studies that suggest a molecular niche for the diaphragm which is quite different from that occupied by limb muscle. All indications are that this is true not only in regard to differential gene transcription patterns in healthy muscles but also in the changes in transcription occurring in association with different diseases.

Genetic CLC-1 chloride channel deficiency modifies diaphragm muscle isometric contractile properties.

Genetic deficiency of the muscle chloride channel CLC-1 leads to myotonia congenita in humans as well as myotonia in mice and goats. The hallmark of myotonia is delayed muscle relaxation due to persistent electrical discharges in the muscle. The present study tested the hypothesis that performance of CLC-1 deficient diaphragm muscle is also altered during the contractile phase of the contraction-relaxation cycle.

Gene expression profiling of diaphragm muscle in alpha2-laminin (merosin)-deficient dy/dy dystrophic mice.

Deficiency of alpha2-laminin (merosin) underlies classical congenital muscular dystrophy in humans and dy/dy muscular dystrophy in mice and causes severe muscle dysfunction in both species. To gain greater insight into the biochemical and molecular events that link alpha2-laminin deficiency with muscle fiber necrosis, and the associated compensatory responses, gene expression profiles were characterized in diaphragm muscle from 8-wk-old dy/dy mice using oligonucleotide microarrays. Compared with age-matched normal muscle, dystrophic diaphragm was characterized by predominantly augmented gene expression, irrespective of the fold-change threshold.

Altered diaphragm muscle action potentials in Zucker diabetic fatty (ZDF) rats.

The Zucker diabetic fatty (ZDF) rat is a model of type 2 diabetes, being characterized by obesity, diabetes, and dyslipidemia. In vitro studies tested the hypothesis that diaphragm muscle from ZDF rats has abnormal resting membrane potential and action potentials, similar to type 1 diabetic rodents. Resting membrane potential was comparable for muscle from ZDF and control rats.

Modulation of biphasic rate of end-plate potential recovery in rat diaphragm.

Previous diaphragm studies found that during intermittent stimulation, intratrain end-plate potential (EPP) amplitude rundown is accelerated by increasing stimulation frequency, whereas intertrain EPP rundown is independent of frequency. We hypothesized that increasing stimulation frequency accelerates rundown recovery, and with a biphasic time course. Intracellular recordings were made in vitro from rat phrenic nerve-hemidiaphragm preparations.

Reduced amount and disrupted temporal pattern of spontaneous exercise in diabetic rats.

Introduction/purpose: The beneficial effects of exercise for subjects with diabetes or prediabetic states are well established. However, the converse, that is, the effect of diabetes on spontaneous exercise performance, is not as well defined. Mice with mdx muscular dystrophy not only reduce total spontaneous running distance, but also decrease the duration of periods during which they are active, suggesting a defect in endurance.