Detrusor underactivity causes neurogenic voiding dysfunction in a rat bilateral accessory nerve-injury model.

We aimed to investigate detrusor function in a previously developed rat neurogenic voiding dysfunction model that we have developed previously. We performed sham or bilateral accessory nerve injury (BACNI) surgeries on ten-week-old male Wistar/ST rats. One week after surgery, we evaluated detrusor contractility in the bladder using isometric tension and mRNA expression assays. Cholinergic contraction was attenuated in the injury model, whereas carbachol-evoked contraction was enhanced, and mRNA expression of the cholinergic receptor increased. These findings suggest that there was a reduction in neurotransmitter release causing detrusor underactivity.

Do Actomyosin Single-Molecule Mechanics Data Predict Mechanics of Contracting Muscle?

In muscle, but not in single-molecule mechanics studies, actin, myosin and accessory proteins are incorporated into a highly ordered myofilament lattice. In view of this difference we compare results from single-molecule studies and muscle mechanics and analyze to what degree data from the two types of studies agree with each other. There is reasonable correspondence in estimates of the cross-bridge power-stroke distance (7⁻13 nm), cross-bridge stiffness (~2 pN/nm) and average isometric force per cross-bridge (6⁻9 pN). Furthermore, models defined on the basis of single-molecule mechanics and solution biochemistry give good fits to experimental data from muscle. This suggests that the ordered myofilament lattice, accessory proteins and emergent effects of the sarcomere organization have only minor modulatory roles. However, such factors may be of greater importance under e.g., disease conditions. We also identify areas where single-molecule and muscle data are conflicting: (1) whether force generation is an Eyring or Kramers process with just one major power-stroke or several sub-strokes; (2) whether the myofilaments and the cross-bridges have Hookean or non-linear elasticity; (3) if individual myosin heads slip between actin sites under certain conditions, e.g., in lengthening; or (4) if the two heads of myosin cooperate.

Effects of the ACTN3 R577X Genotype on the Muscular Strength and Range of Motion Before and After Eccentric Contractions of the Elbow Flexors.

The purpose of present study was to examine the association between ACTN3 R577X genotype and functional characteristics of elbow flexors before and after isokinetic eccentric contractions (ECCs). Fifty-two men (age: 20.8±3.8 years, height: 172.5±5.9 cm, body mass: 64.7±6.5 kg, BMI: 21.7±1.7) who had not participated in any regular resistance training for at least 1 year prior to this study were recruited. ECCs consisted of five sets of six maximal voluntary isokinetic (30°/s) ECCs of the elbow flexors with a range of motion (ROM) from 90° flexion to 0° (full extension). Measurements of maximal voluntary isometric contraction (MVC) torque, ROM, and muscle soreness were taken before, immediately after, and 1, 2, 3, and 5 days after ECCs. Genotyping results were analyzed for identifying ACTN3 R577X polymorphism (rs1815739) using TaqMan approach. The genotype frequencies of the ACTN3 R577X polymorphism were RR 26.9% (n=14), RX 50.0% (n=26), and XX 23.1% (n=12). There were no significant differences in MVC torque, ROM, and soreness between three genotype groups of ACTN3 R577X. However, MVC at baseline was greater in RR homozygotes than in X-allele carriers (combined XX and RX; p<0.05). ROM in RR homozygotes at baseline was lower than that of X-allele carriers. Although a significant decrease in ROM was observed in X-allele carriers until 3 days after ECCs, a significant ROM reduction in RR homozygotes was observed only immediately after ECCs. Our data indicated that ACTN3 RR genotype has higher MVC and lower flexibility than X-allele carriers at baseline, but the effect of ACTN3 R577X genotype on these two parameters is limited after ECCs.

Single and modeled multifrequency electrical impedance myography parameters and their relationship to force production in the ALS SOD1G93A mouse.

OBJECTIVE: The relationship between muscle force production in ALS SOD1G93A mice and single and modeled multifrequency electrical impedance myography (EIM) parameters is unknown. We evaluated the relationship between multifrequency EIM data and paw grip and in situ force measurements, as well to standard measures including body weight and compound motor action potential (CMAP) amplitude. METHODS: Twenty-nine SOD1 G93A mice aged 13-18 weeks (approximately 4-5 per week) and a group of similarly aged wild-type mice (N = 7) were studied with single and multifrequency EIM, CMAP, front and hind-limb paw grip measures, and in situ force measurements of the gastrocnemius. RESULTS: Significant differences among WT, presymptomatic, and symptomatic ALS animals were identified for all standard measures and single 50 kHz frequency EIM parameters. Of the modeled multifrequency measures, the center frequency, fc , an index of cell size, showed the strongest relationship to force output. The two other multifrequency parameters corresponding to cell size distribution and cell density showed consistent although mostly non-significant differences. CONCLUSION: Reductions in force are reflected in single 50 kHz impedance values and in the fc. These data support the construct validity of EIM as an assessment tool of muscle dysfunction in diseases associated with motor neuron loss.

Anodal transcranial direct current stimulation of the motor cortex increases cortical voluntary activation and neural plasticity.

INTRODUCTION: We examined the cumulative effect of 4 consecutive bouts of noninvasive brain stimulation on corticospinal plasticity and motor performance, and whether these responses were influenced by the brain-derived neurotrophic factor (BDNF) polymorphism. METHODS: In a randomized double-blinded cross-over design, changes in strength and indices of corticospinal plasticity were analyzed in 14 adults who were exposed to 4 consecutive sessions of anodal and sham transcranial direct current stimulation (tDCS). Participants also undertook a blood sample for BDNF genotyping (N = 13). RESULTS: We observed a significant increase in isometric wrist flexor strength with transcranial magnetic stimulation revealing increased corticospinal excitability, decreased silent period duration, and increased cortical voluntary activation compared with sham tDCS. CONCLUSIONS: The results show that 4 consecutive sessions of anodal tDCS increased cortical voluntary activation manifested as an improvement in strength. Induction of corticospinal plasticity appears to be influenced by the BDNF polymorphism. Muscle Nerve 54: 903-913, 2016.

Characterizations of the α1-adrenoceptor subtypes mediating contractions of the human internal anal sphincter.

Human internal anal sphincter (IAS) is contracted by α1-adrenoceptor stimulation and thus α1-adrenoceptor agonists may be useful in treating fecal incontinence. This study characterizes the contribution of α1-adrenoceptor subtypes in contraction of human IAS and to investigate the age-related risk of patients with fecal incontinence. IAS and inferior mesenteric artery (IMA), as a predictor of systemic arterial pressure, were obtained from 11 patients. Both muscle strips were assessed by isometric-contraction experiments using phenylephrine, further in IAS, in the presence of various subtype selective α1-adrenoceptor antagonists. Immunohistochemistry and gene expression studies were performed in the same samples. The mean pEC50 values with SEM of phenylephrine in IAS (6.30 ± 0.13) were higher than those of IMA (5.60 ± 0.10). Furthermore, the age-related pEC50 change of IAS was observed between age <70 and ≥70 (6.58 ± 0.13 and 6.07 ± 0.16, respectively (P < 0.05)). In IAS, rightward shift of the concentration-response curves of phenylephrine was observed with three α1-adrenoceptor antagonists. Each pKB value of silodosin, BMY-7378 and prazosin was 9.36 ± 0.53, 7.28 ± 0.20 and 8.89 ± 0.12, respectively. These pKB values and gene expression studies indicated that α1A-adrenoceptor subtypes predominantly contributed to human IAS contraction.

Sexually dimorphic myofilament function in a mouse model of nemaline myopathy.

Nemaline myopathy, the most common congenital myopathy, is characterized by mutations in genes encoding myofilament proteins such as skeletal α-actin. These mutations are thought to ultimately lead to skeletal muscle weakness. Interestingly, some of the mutations appear to be more potent in males than in females. The underlying mechanisms remain obscure but may be related to sex-specific differences in the myofilament function of both limb and respiratory muscles. To verify this, in the present study, we used skeletal muscles (tibialis anterior and diaphragm) from a transgenic mouse model harbouring the His40Tyr amino acid substitution in skeletal α-actin. In this animal model, 60% of males die by 13weeks of age (the underlying causes of death are obscure but probably due to respiratory insufficiency) whereas females have a normal lifespan. By recording and analysing the mechanics of membrane-permeabilized myofibres, we only observed sex-related differences in the tibialis anterior muscles. Indeed, the concomitant deficits in maximal steady-state isometric force and stiffness of myofibres were less exacerbated in transgenic females than in males, potentially explaining the lower potency in limb muscles. However, the absence of sex-difference in the diaphragm muscles was rather unexpected and suggests that myofilament dysfunction does not solely underlie the sexually dimorphic phenotypes.

Beneficial effects of bumetanide in a CaV1.1-R528H mouse model of hypokalaemic periodic paralysis.

Transient attacks of weakness in hypokalaemic periodic paralysis are caused by reduced fibre excitability from paradoxical depolarization of the resting potential in low potassium. Mutations of calcium channel and sodium channel genes have been identified as the underlying molecular defects that cause instability of the resting potential. Despite these scientific advances, therapeutic options remain limited. In a mouse model of hypokalaemic periodic paralysis from a sodium channel mutation (NaV1.4-R669H), we recently showed that inhibition of chloride influx with bumetanide reduced the susceptibility to attacks of weakness, in vitro. The R528H mutation in the calcium channel gene (CACNA1S encoding CaV1.1) is the most common cause of hypokalaemic periodic paralysis. We developed a CaV1.1-R528H knock-in mouse model of hypokalaemic periodic paralysis and show herein that bumetanide protects against both muscle weakness from low K+ challenge in vitro and loss of muscle excitability in vivo from a glucose plus insulin infusion. This work demonstrates the critical role of the chloride gradient in modulating the susceptibility to ictal weakness and establishes bumetanide as a potential therapy for hypokalaemic periodic paralysis arising from either NaV1.4 or CaV1.1 mutations.

Smooth muscle-selective CPI-17 expression increases vascular smooth muscle contraction and blood pressure.

Recent data revealed that protein kinase C-potentiated myosin phosphatase inhibitor of 17 kDa (CPI-17), a myosin phosphatase inhibitory protein preferentially expressed in smooth muscle, is upregulated/activated in several diseases but whether this CPI-17 increase plays a causal role in pathologically enhanced vascular smooth muscle contractility and blood pressure remains unclear. To address this possibility, we generated a smooth muscle-specific CPI-17 transgenic mouse model (CPI-17-Tg) and demonstrated that the CPI-17 transgene was selectively expressed in smooth muscle-enriched tissues, including mesenteric arteries. The isometric contractions in the isolated second-order branch of mesenteric artery helical strips from CPI-17-Tg mice were significantly enhanced compared with controls in response to phenylephrine, U-46619, serotonin, ANG II, high potassium, and calcium. The perfusion pressure increases in isolated perfused mesenteric vascular beds in response to norepinephrine were also enhanced in CPI-17-Tg mice. The hypercontractility was associated with increased phosphorylation of CPI-17 and 20-kDa myosin light chain under basal and stimulated conditions. Surprisingly, the protein levels of rho kinase 2 and protein kinase Cα/δ were significantly increased in CPI-17-Tg mouse mesenteric arteries. Radiotelemetry measurements demonstrated that blood pressure was significantly increased in CPI-17-Tg mice. However, no vascular remodeling was detected by morphometric analysis. Taken together, our results demonstrate that increased CPI-17 expression in smooth muscle promotes vascular smooth muscle contractility and increases blood pressure, implicating a pathological significant role of CPI-17 upregulation.

Aerobic exercise does not compromise muscle hypertrophy response to short-term resistance training.

This study tested the hypothesis that chronic aerobic and resistance exercise (AE+RE) would elicit greater muscle hypertrophy than resistance exercise only (RE). Ten men (25 ± 4 yr) performed 5 wk unilateral knee extensor AE+RE. The opposing limb was subjected to RE. AE completed 6 hr prior to RE consisted of ~45 min one-legged cycle ergometry. RE comprised 4 × 7 maximal concentric-eccentric knee extensions. Various indexes of in vivo knee extensor function were measured before and after training. Magnetic resonance imaging (MRI) assessed m. quadricep femoris (QF) cross-sectional area (CSA), volume, and signal intensity (SI). Biopsies obtained from m. vastus lateralis determined fiber CSA, enzyme levels, and gene expression of myostatin, atrogin-1, MuRF-1, PGC-1α, and VEGF. Increases (P < 0.05) in isometric strength and peak power, respectively, were comparable in AE+RE (9 and 29%) and RE (11 and 24%). AE+RE showed greater increase (14%; P < 0.05) in QF volume than RE (8%). Muscle fiber CSA increased 17% after AE+RE (P < 0.05) and 9% after RE (P > 0.05). QF SI increased (12%; P < 0.05) after AE+RE, but not RE. Neither AE+RE nor RE showed altered mRNA levels. Citrate synthase activity increased (P < 0.05) after AE+RE. The results suggest that the increased aerobic capacity shown with AE+RE was accompanied by a more robust increase in muscle size compared with RE. Although this response was not carried over to greater improvement in muscle function, it remains that intense AE can be executed prior to RE without compromising performance outcome.

A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis.

Hypokalemic periodic paralysis (HypoPP) is an ion channelopathy of skeletal muscle characterized by attacks of muscle weakness associated with low serum K+. HypoPP results from a transient failure of muscle fiber excitability. Mutations in the genes encoding a calcium channel (CaV1.1) and a sodium channel (NaV1.4) have been identified in HypoPP families. Mutations of NaV1.4 give rise to a heterogeneous group of muscle disorders, with gain-of-function defects causing myotonia or hyperkalemic periodic paralysis. To address the question of specificity for the allele encoding the NaV1.4-R669H variant as a cause of HypoPP and to produce a model system in which to characterize functional defects of the mutant channel and susceptibility to paralysis, we generated knockin mice carrying the ortholog of the gene encoding the NaV1.4-R669H variant (referred to herein as R669H mice). Homozygous R669H mice had a robust HypoPP phenotype, with transient loss of muscle excitability and weakness in low-K+ challenge, insensitivity to high-K+ challenge, dominant inheritance, and absence of myotonia. Recovery was sensitive to the Na+/K+-ATPase pump inhibitor ouabain. Affected fibers had an anomalous inward current at hyperpolarized potentials, consistent with the proposal that a leaky gating pore in R669H channels triggers attacks, whereas a reduction in the amplitude of action potentials implies additional loss-of-function changes for the mutant NaV1.4 channels.

Melatonin improves muscle function of the dystrophic mdx5Cv mouse, a model for Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a severe X-linked muscle-wasting disease caused by the absence of the cytoskeletal protein dystrophin. In addition to abnormal calcium handling, numerous studies point to a crucial role of oxidative stress in the pathogenesis of the disease. Considering the impressive results provided by antioxidants on dystrophic muscle structure and function, we investigated whether melatonin can protect the mdx(5Cv) mouse, an animal model for DMD. Male mdx(5Cv) mouse pups were treated with melatonin by daily intraperitoneal (i.p.) injection (30 mg/kg body weight) or by subcutaneous (s.c.) implant(s) (18 or 54 mg melatonin as Melovine® implants) from 17/18 to 28/29 days of age. Isometric force of the triceps surae was recorded at the end of the treatment. The i.p. treatment increased the phasic twitch tension of mdx(5Cv) mice. The maximal tetanic tension was ameliorated by 18 mg s.c. and 30 mg/kg i.p. treatments. Melatonin caused the dystrophic muscle to contract and relax faster. The force-frequency relationship of melatonin-treated dystrophic mice was shifted to the right. In accordance with improved muscle function, melatonin decreased plasma creatine kinase activity, a marker for muscle injury. Melatonin treatment increased total glutathione content and lowered the oxidized/reduced glutathione ratio, indicating a better redox status of the muscle. In light of the present investigation, the therapeutic potential of melatonin should be further considered for patients with DMD.

Comparison of the function of the serotonin transporter in the vasculature of male and female rats.

1. The serotonin transporter (SERT) handles serotonin (5-hydroxytryptamine (5-HT)) and is blocked by the antidepressant SERT inhibitors fluoxetine and fluvoxamine. Although the importance of SERT in the central nervous system is clear, SERT also functions in the peripheral vasculature. In the present study, we tested the hypothesis that the vasculature from female rats has increased SERT function compared with male rats because females are more responsive to SERT inhibitors. 2. In addition to in vitro experiments, in vivo experiments were used to evaluate how male and female rats handle chronically elevated levels of 5-HT. Wild-type (WT) and SERT-knockout (SERT-KO) rats were infused with 5-HT (25 µg/kg per min) for 7 days by minipump. 3. Using HPLC analysis, we demonstrated that blood vessels (aorta, carotid artery, jugular vein and vena cava) from naïve, non-infused female rats took up 5-HT acutely in vitro in a SERT-dependent manner. In in vitro experiments, SERT affected the contractility of aortas from female rats, as evidenced by an eightfold increase in potency of 5-HT in fluvoxamine (1 µmol/L)-incubated WT aortas compared with control. Fluvoxamine did not alter 5-HT-induced contraction in aortas from SERT-KO female rats. 4. Infusion of 5-HT resulted in an increase in tissue 5-HT that was reduced to a larger extent in blood vessels from female than male SERT-KO rats. Aortic contractions to 5-HT were abolished in aortas from male and female 5-HT-infused SERT-KO rats compared with WT rats. 5. Collectively, these data suggest that SERT function, when challenged with 5-HT, is modestly more important in the vasculature of the female compared with male rat.

The effect of skeletal myosin light chain kinase gene ablation on the fatigability of mouse fast muscle.

Contraction-induced activation of a skeletal muscle specific Ca(2+) and calmodulin dependent myosin light chain kinase (skMLCK) catalyzes phosphorylation of the myosin regulatory light chain (RLC), a reaction that potentiates twitch force. The purpose of this study was to test the effect of skMLCK gene ablation on the fatigability of mouse extensor digitorum longus (EDL) muscle (in vitro at 25°C). Muscles were isolated from wildtype (WT, n = 10-12) and skeletal MLCK knockout (skMLCK KO, n = 10-12) mice and fatigued using a protocol consisting of 5 min of repeated tetanic stimulation (150 Hz for 1000 ms every 5 s). Both twitch (P(t)) and tetanic (P(o)) force as well as unloaded shortening velocity (V(o)) were assessed before, during and after fatiguing stimulation. Fatiguing stimulation increased RLC phosphorylation in WT but not skMLCK KO muscles (16 ± 0.01-0.63 ± 0.02 and 0.07 ± 0.02-0.08 ± 0.02 mol phos mol RLC, respectively). Although P(t) was potentiated above baseline in both WT and KO muscles, this increase was greater in WT than in KO muscles (to 1.37 ± 0.05 vs. 1.14 ± 0.02 of unpotentiated values, respectively). The difference in P(t) persisted until P(o) had been diminished to ~60% of baseline and thereafter P(t) declined to similar levels in both WT and KO muscles (to ~35% of initial). Overall, the time-course and decline in P(o) for WT and KO was similar (reduced to 0.20 ± 0.01 and 0.20 ± 0.01 of baseline, respectively) (P < 0.05). Initial values for V(o) were similar between WT and KO muscles and, moreover, the fatigue related decline in Vo was similar for both muscle genotypes (P < 0.05). Thus, our results demonstrate that skMLCK--catalyzed RLC phosphorylation augments isometric twitch force during moderate, but not severe, levels of fatigue.

Responses of muscle mass, strength and gene transcripts to long-term heat stress in healthy human subjects.

The present study was performed to investigate the effects of long-term heat stress on mass, strength and gene expression profile of human skeletal muscles without exercise training. Eight healthy men were subjected to 10-week application of heat stress, which was performed for the quadriceps muscles for 8 h/day and 4 days/week by using a heat- and steam-generating sheet. Maximum isometric force during knee extension of the heated leg significantly increased after heat stress (~5.8%, P < 0.05). Mean cross-sectional areas (CSAs) of vastus lateralis (VL, ~2.7%) and rectus femoris (~6.1%) muscles, as well as fiber CSA (8.3%) in VL, in the heated leg were also significantly increased (P < 0.05). Statistical analysis of microarrays (SAM) revealed that 10 weeks of heat stress increased the transcript level of 925 genes and decreased that of 1,300 genes, and gene function clustering analysis (Database for Annotation, Visualization and Integrated Discovery: DAVID) showed that these regulated transcripts stemmed from diverse functional categories. Transcript level of ubiquinol-cytochrome c reductase binding protein (UQCRB) was significantly increased by 10 weeks of heat stress (~3.0 folds). UQCRB is classified as one of the oxidative phosphorylation-associated genes, suggesting that heat stress can stimulate ATP synthesis. These results suggested that long-term application of heat stress could be effective in increasing the muscle strength associated with hypertrophy without exercise training.

CCL2 and CCR2 variants are associated with skeletal muscle strength and change in strength with resistance training.

Baseline muscle size and muscle adaptation to exercise are traits with high variability across individuals. Recent research has implicated several chemokines and their receptors in the pathogenesis of many conditions that are influenced by inflammatory processes, including muscle damage and repair. One specific chemokine, chemokine (C-C motif) ligand 2 (CCL2), is expressed by macrophages and muscle satellite cells, increases expression dramatically following muscle damage, and increases expression further with repeated bouts of exercise, suggesting that CCL2 plays a key role in muscle adaptation. The present study hypothesizes that genetic variations in CCL2 and its receptor (CCR2) may help explain muscle trait variability. College-aged subjects [n = 874, Functional Single-Nucleotide Polymorphisms Associated With Muscle Size and Strength (FAMUSS) cohort] underwent a 12-wk supervised strength-training program for the upper arm muscles. Muscle size (via MR imaging) and elbow flexion strength (1 repetition maximum and isometric) measurements were taken before and after training. The study participants were then genotyped for 11 genetic variants in CCL2 and five variants in CCR2. Variants in the CCL2 and CCR2 genes show strong associations with several pretraining muscle strength traits, indicating that inflammatory genes in skeletal muscle contribute to the polygenic system that determines muscle phenotypes. These associations extend across both sexes, and several of these genetic variants have been shown to influence gene regulation.

Eccentric contractions induce rapid isometric torque drop in dystrophin-deficient dogs.

We tested the hypothesis that eccentric contractions (ECCs) rapidly induce greater-than-normal isometric torque drop in dystrophin-deficient golden retriever muscular dystrophy (GRMD) muscles. ECCs were imposed by forcibly stretching activated muscles. The results indicate that isometric torque drop was greater in GRMD versus controls (P < 0.0001). Our findings support the hypothesis that ECCs induce greater-than-normal isometric torque drop in GRMD muscles. The magnitude of ECC-induced isometric torque loss may be an ideal clinical endpoint in the GRMD model.

CNTF 1357 G -> A polymorphism and the muscle strength response to resistance training.

The present study examined associations between the ciliary neurotrophic factor (CNTF) 1357 G --> A polymorphism and the muscle strength response to a unilateral, upper arm resistance-training (RT) program among healthy, young adults. Subjects were 754 Caucasian men (40%) and women (60%) who were genotyped and performed a training program of the nondominant (trained) arm with the dominant (untrained) arm as a comparison. Peak elbow flexor strength was measured with one repetition maximum, isometric strength with maximum voluntary contraction, and bicep cross-sectional area with MRI in the trained and untrained arms before and after training. Women with the CNTF GG genotype gained more absolute isometric strength, as measured by MVC (6.5 +/- 0.3 vs. 5.2 +/- 0.5 kg), than carriers of the CNTF A1357 allele in the trained arm pre- to posttraining (P < 0.05). No significant associations were seen in men. Women with the CNTF GG genotype gained more absolute dynamic (1.0 +/- 0.1 vs. 0.6 +/- 0.1 kg) and allometric (0.022 +/- 0.0 vs. 0.015 +/- 0.0 kg/kg(-0.67)) strength, as measured by 1 RM, than carriers of the CNTF A1357 allele in the untrained arm pre- to posttraining (P < 0.05). No significant associations were seen in men. No significant associations, as measured by cross-sectional area, were seen in men or women. The CNTF 1357 G --> A polymorphism explains only a small portion of the variability in the muscle strength response to training in women.

Upregulation of MHC class I in transgenic mice results in reduced force-generating capacity in slow-twitch muscle.

Expression of major histocompatibility complex (MHC) class I in skeletal muscle fibers is an early and consistent finding in inflammatory myopathies. To test if MHC class I has a primary role in muscle impairment, we used transgenic mice with inducible overexpression of MHC class I in their skeletal muscle cells. Contractile function was studied in isolated extensor digitorum longus (EDL, fast-twitch) and soleus (slow-twitch) muscles. We found that EDL was smaller, whereas soleus muscle was slightly larger. Both muscles generated less absolute force in myopathic compared with control mice; however, when force was expressed per cross-sectional area, only soleus muscle generated less force. Inflammation was markedly increased, but no changes were found in the activities of key mitochondrial and glycogenolytic enzymes in myopathic mice. The induction of MHC class I results in muscle atrophy and an intrinsic decrease in force-generation capacity. These observations may have important implications for our understanding of the pathophysiological processes of muscle weakness seen in inflammatory myopathies. Muscle Nerve, 2008.

Genetic and environmental effects on isometric muscle strength and leg extensor power followed up for three years among older female twins.

The purpose of this study was to examine changes in the contribution of genetic and environmental effects to isometric knee extensor strength and leg extensor power among 63- to 76-year-old female twins over a 3-yr follow-up. At baseline in 2000 the sample comprised 206 monozygotic (MZ) and 228 dizygotic (DZ) twin individuals, and at follow-up in 2003 the sample comprised 149 MZ and 164 DZ twin individuals. Genetic modeling showed that genetic effects explained 58% (95% CI: 46-68%) of the variance in muscle strength at baseline and 56% (95% CI: 41-68%) at follow-up, with no occasion-specific genetic effect. Nonshared environmental effects accounted for 42% (95% CI: 32-54%) of the variation at baseline and 15% (95% CI: 7-26%) at follow-up. In addition, new nonshared environmental effects explained the remaining variance, 29% (95% CI: 22-37%) of muscle strength at follow-up. For muscle power, the same genetic effects accounted for 67% (95% CI: 57-74%) of the variation at baseline and 48% (95% CI: 34-61%) at follow-up. Nonshared environmental effects in common at both measurement points explained 33% (95% CI: 25-43%) of the total variation at baseline and 11% (95% CI: 5-21%) at follow-up. The remaining variance of muscle power at follow-up was accounted for by time-specific environmental effects. Results indicated that the contribution of genetic effects to isometric muscle strength was stable, whereas for leg extensor power the proportion of genetic effects decreased during the follow-up. We observed new specific environmental effects underlying follow-up muscle strength and power, which effects could be due to the onset of new disease processes or changes in lifestyle.