Mechanisms Of Muscle Weakness Research Articles

Compromised Muscle Properties in a Severe Hypophosphatasia Murine Model.

Hypophosphatasia (HPP) is a rare metabolic bone disorder characterized by low levels of tissue non-specific alkaline phosphatase (TNAP) that causes under-mineralization of the bone, leading to bone deformity and fractures. In addition, patients often present with chronic muscle pain, reduced muscle strength, and an altered gait. In this work, we explored dynamic muscle function in a homozygous TNAP knockout mouse model of severe juvenile onset HPP. We found a reduction in skeletal muscle size and impairment in a range of isolated muscle contractile properties. Using histological methods, we found that the structure of HPP muscles was similar to healthy muscles in fiber size, actin and myosin structures, as well as the α-tubulin and mitochondria networks. However, HPP mice had significantly fewer embryonic and type I fibers than wild type mice, and fewer metabolically active NADH+ muscle fibers. We then used oxygen respirometry to evaluate mitochondrial function and found that complex I and complex II leak respiration were reduced in HPP mice, but that there was no disruption in efficiency of electron transport in complex I or complex II. In summary, the severe HPP mouse model recapitulates the muscle strength impairment phenotypes observed in human patients. Further exploration of the role of alkaline phosphatase in skeletal muscle could provide insight into mechanisms of muscle weakness in HPP.

Impact of aging and oxidative stress on specific components of excitation contraction coupling in regulating force generation

Muscle weakness associated with sarcopenia is a major contributor to reduced health span and quality of life in the elderly. However, the underlying mechanisms of muscle weakness in aging are not fully defined. We investigated the effect of oxidative stress and aging on specific molecular mechanisms involved in muscle force production in mice and skinned permeabilized single fibers in mice lacking the antioxidant enzyme CuZnSod (Sod1KO) and in aging (24-month-old) wild-type mice. Loss of muscle strength occurs in both models, potentially because of reduced membrane excitability with altered NKA signaling and RyR stability, decreased fiber Ca2+ sensitivity and suppressed SERCA activity via modification of the Cys674 residue, dysregulated SR and cytosolic Ca2+ homeostasis, and impaired mitochondrial Ca2+ buffering and respiration. Our results provide a better understanding of the specific impacts of aging and oxidative stress on mechanisms related to muscle weakness that may point to future interventions for countering muscle weakness.

Relationship of the sacral slope with early gait derangements in robust older women

BackgroundTrunk pelvic dissociation is fundamental to the compensatory mechanism for muscle weakness during body bending. We carried out an early investigation of gait changes in a sample of community-dwelling women ≥60 years without gait complaints. The primary objective was to correlate spine and pelvic angles with performance tests and accelerometry parameters. The secondary objective was to correlate performance tests with accelerometry.MethodsIn this cross-sectional study, 54 community-dwelling women ≥60 years were subjected to Falls Efficacy Scale-International (FES-I), performance tests (Berg Balance Scale, Timed Up and Go, and Gait analysis), and radiographic analysis of sagittal alignment (Thoracic and Lumbar Cobb, Pelvic Incidence, Sacral Slope, and Pelvic Tilt angles). Gait speed was assessed in a 10-m comfortable walk, and accelerometry parameters were obtained in a 30-m walk distance.ResultsThe sample, aged 72 ± 6 years, exhibited moderate correlation between Sacral Slope and Step Length (+ 0.615). Sacral Slope weakly correlated with FES-I (− 0.339), Berg Balance Scale (+ 0.367), and with further accelerometry data in the AP plane: RMS, (+ 0.439) and Stride Regularity (+ 0.475), p < 0.05, all. Lumbar Cobb weakly correlated with the following accelerometry data in the AP plane: Step Length (+ 0.405), RMS, (+ 0.392), and Stride Regularity (+ 0.345), p < 0.05, all. Additionally, Stride Regularity in AP moderately correlated with FES-I (0,561, p < 0.05), among other weak correlations between performance tests and accelerometry data in AP.ConclusionsEarly alterations in Sacral Slope and gait abnormalities in the AP plane may provide understanding of the early gait changes in robust older women.

Age-Related Changes in Molecular and Whole Muscle Function: Role of Fat Content?

Decreases in muscle size and function are a general consequence of old age; the precise mechanisms of these changes remain unclear. Recent studies suggest that fat deposition in muscle may also contribute to dysfunction in older adults. Fat content was quantified in the quadriceps, and its effects on function in healthy young (21-45 y) and older (65-75 y) men and women (n=44) of comparable physical activity were compared. A subset of the young matched with the older group for muscle fat content were also examined. Peak fat-free whole muscle cross-sectional area (mCSA; cm2), volume (MV; cm3), fat content (fat fraction, FF; %), specific torque (Nm/mCSA) and peak contraction velocity (Nm∙s-1) were determined using fat-water magnetic resonance imaging and dynamometry (0-300□∙s-1). To examine potential molecular mechanisms of muscle weakness, vastus lateralis biopsies were obtained (n=31) and cross-bridge kinetics of type I and II fibers were determined. FF was higher in older adults than young (8.4±1.2% (SE), 7.6±1.4; p=0.03), while mCSA (48.9±10.4 vs. 64.2±17.3), MV (1536±532 vs. 2112±708), specific torque (2.6±0.4 vs. 3.2±0.4), and peak voluntary contraction velocity (422±20 vs. 441±23) were lower in older than young (p<0.01). Type II fiber myosin attachment rate was slower and attachment time longer in older muscle (p<0.017), providing a potential mechanism for the slowing of peak contraction velocity with age. Notably, differences at the whole muscle and molecular levels remained for the subset of young and older groups matched for FF, suggesting that fat deposition in muscle does not exacerbate age-related changes in function.

White matter damage and altered connectivity between primary motor cortices in chronic obstructive pulmonary disease.

White matter damage and altered connectivity between primary motor cortices in chronic obstructive pulmonary disease.

EEG-EMG Correlation for Parkinson’s disease

Parkinson's disease (PD) is a neurodegenerative disease in which disease symptoms progresses with time and mostly affected after 50 years of age. This disorder leads to loss of interconnectivity between brain and muscles. Human Biosignal like Electroencephalography (EEG) and Electromyography (EMG) acts as a tool for detecting various cognitive decline and muscle conditions in PD. Work reported here emphasized on a study of the EEG from the frontal and temporal brain in PD and healthy subjects as well as their muscle activities for the flexion and extension of the wrist. Signal acquisition was done using a dual channel Biosignal acquisition system from AD Instruments. Signals were acquired for 30 minutes each for all the subjects in the Out Patient Departments of various hospitals. Signal analysis was carried out in MATLAB platform. Various EEG and EMG features were extracted to determine brain and muscle conditions of patients. Classification was done using Artificial Neural Network for EEG and EMG features separately. A combination of EEG and EMG feature was also classified using ANN which gave a highest classification rate of 98.8% as compared to only EEG and EMG feature. This result proved that correlation and combination of various EEG and EMG features together provides more accuracy to the disease classifier. It gives an insight into the mechanism of muscle weakness and gait problems caused from the low production of dopamine in the brain of PD by giving a high classification rate as compared to others(Only EEG features and Only EMG features). Many studies have reviled the effect of EEG and EMG using various tools but here we focus mainly on correlation between them in the early stages. Detection of conditions of brain and muscle in early stage helps the clinician for proper medication to control disease progression. This work can also be further applicable for classifying the various stages of PD and also classifying them from the healthy subjects.

155 Sex-related differences in muscle co-activation in individuals with knee osteoarthritis

Background: Sex-related differences in muscle function have been well established in healthy individuals. In individuals with knee osteoarthritis (KOA), impairments in muscle function such as muscle weakness and high muscle co-activation have also been demonstrated. Muscle dysfunction has been shown to be a strong contributor to poor physical function and low health-related quality of life in patients with KOA. The purpose of this study was, therefore, to analyse sex and osteoarthritis-related differences in muscle function, to establish to what extent both sex and disease status contribute to muscle dysfunction. Methods: Muscle co-activation was assessed in 77 symptomatic KOA participants (62.5±8.1yrs; 48/29 women/men) and 18 age-matched asymptomatic controls (62.5±10.4yrs; 9/9 women/men), using electromyography (EMG) during a series of walking, stair ascent and descent and sit-to-walk activities. EMG was recorded from 7 sites medial/lateral gastrocnemius, biceps femoris, semitendinosus, vastus lateralis/medialis and normalised to maximal voluntary contraction. Normalised EMG was used to calculate hamstrings-quadriceps and medial-lateral muscle co-activation as (antagonist/agonist) *(antagonist+agonist). The stance phase of walking was split into pre-stance (150ms prior to initial contact), loading (0-15% of stance), early-stance (15-40%), mid-stance (40-60%), late-stance (60-100%) and overall-stance (0-100%). Stairs negotiation was also split into transition (stance phase on the floor) and continuous (stance phase on the second step of the staircase). All participants provided written informed consent and the study was approved by Research Ethics committees (HLS12/86, 13/ws/0146). Independent samples T-tests were performed to assess the differences between KOA and controls. Linear regressions were performed to investigate the relationship between muscle function, sex and disease status, and Bonferroni corrected for multiple comparisons. Results: Individuals with KOA were weaker than controls (P < 0.007). Overall there were very few differences in muscle co-activation between KOA and controls. Women were weaker than men (P ⩽ 0.002) and had higher hamstrings-quadriceps and medial-lateral muscle co-activation across all activities of daily living. In multiple regression analyses sex and muscle weakness, but not age or disease status, predicted high muscle co-activation. Conclusion: High muscle co-activation was associated with female sex and muscle weakness regardless of disease status and age. It has previously been suggested that muscle co-activation acts as a compensatory mechanism for muscle weakness, accommodating for the diminished force generating capabilities to maintain a certain level of function and movement activation patterns. This suggests that muscle weakness may be the main contributing factor for high muscle co-activation which is thought to increase joint loads with detrimental effects on cartilage and joint integrity. This may explain high muscle co-activation in women with muscle weakness and increased risk of incidence and progression of KOA in women.

Advances in the understanding of skeletal muscle weakness in murine models of diseases affecting nerve-evoked muscle activity, motor neurons, synapses and myofibers

Disease processes and trauma affecting nerve-evoked muscle activity, motor neurons, synapses and myofibers cause different levels of muscle weakness, i.e., reduced maximal force production in response to voluntary activation or nerve stimulation. However, the mechanisms of muscle weakness are not well known. Using murine models of amyotrophic lateral sclerosis (SOD1G93A transgenic mice), congenital myasthenic syndrome (AChE knockout mice and MuskV789M/− mutant mice), Schwartz–Jampel syndrome (Hspg2C1532YNEO/C1532YNEO mutant mice) and traumatic nerve injury (Neurotomized wild-type mice), we show that the reduced maximal activation capacity (the ability of the nerve to maximally activate the muscle) explains 52%, 58% and 100% of severe weakness in respectively SOD1G93A, Neurotomized and Musk mice, whereas muscle atrophy only explains 37%, 27% and 0%. We also demonstrate that the impaired maximal activation capacity observed in SOD1, Neurotomized, and Musk mice is not highly related to Hdac4 gene upregulation. Moreover, in SOD1 and Neurotomized mice our results suggest LC3, Fn14, Bcl3 and Gadd45a as candidate genes involved in the maintenance of the severe atrophic state. In conclusion, our study indicates that muscle weakness can result from the triggering of different signaling pathways. This knowledge may be helpful in designing therapeutic strategies and finding new drug targets for amyotrophic lateral sclerosis, congenital myasthenic syndrome, Schwartz–Jampel syndrome and nerve injury.

P.9.12 Exploring the pathological mechanism of Actin myopathies in zebrafish

Congenital myopathies are characterized by progressive muscle weakness and low muscle tone. Mutations in ACTA1 are responsible for up to 20% of all congenital myopathies ranging in severity from long-term survival with minor muscle weakness to lethality prior to or shortly after birth. To date over 200 different ACTA1 mutations have been described. At the cellular level ACTA1 mutations result in multiple pathologies including; nemaline bodies, intranuclear rods, actin aggregates, congenital fibre type disproportion, or cores, however, the exact pathophysiology of muscle weakness remains unknown. To investigate the mechanism by which mutations results in the distinct pathologies we have generated stable transgenic zebrafish strains expressing human ACTA1 tagged with GFP. We show, that expression of ACTA1 variants in zebrafish recapitulates the histo-pathological hallmarks of their respective diseases. Using the advantages of the zebrafish model system we followed the progression of disease in vivo and identified distinct mechanisms of muscle weakness. We show that in ACTA1D286G-GFP fish, nemaline bodies initiate as punctate actin aggregations at the muscle attachment sites before elongating to form the characteristic rod shape. In addition to its inclusion in rods, ACTA1D286G-GFP is incorporated into sarcomeres, which is the likely cause of muscle weakness. By contrast the formation of actin aggregates in ACTA1D154N myopathy occurs in the cytoplasm without a clearly defined site of origin and aggregates remain punctate, never elongating to form rods. The accumulation of aggregates triggers cell death leading to muscle weakness. The generation of zebrafish models and identification of distinct mechanisms of disease provides an experimental platform for the development, testing and specific targeting of potential therapies to combat Actin myopathies.

Relationship between muscle volume and muscle torque of the hamstrings after anterior cruciate ligament lesion

This study was conducted to identify factors other than morphological muscle strength factors that affect injured and uninjured sides of knee flexors with anterior cruciate ligament (ACL) lesions. The study population consisted of 22 patients with ACL lesions. Their hamstring muscle volume was measured on MRI, and muscle torque per muscle volume was calculated as the peak torque of knee flexion divided by hamstring muscle volume. The mean muscle torque per unit volume of hamstrings in patients with ACL rupture was 0.09±0.02Nm/cm(3) at 60°/s and 0.08±0.01Nm/cm(3) at 180°/s on the injured side, and 0.11±0.02Nm/cm(3) at 60°/s and 0.08±0.01Nm/cm(3) at 180°/s on the uninjured side. The mean muscle torque per unit volume of hamstrings in control subjects was 0.11±0.02Nm/cm(3) at 60°/s and 0.08±0.03Nm/cm(3) at 180°/s. One-factor ANOVA analysis found no significant differences between the three groups at either flexion velocity. Neurological dysfunction does not appear to exist in knee flexor muscles after ACL injury, unlike the quadriceps. Since the mechanism of muscle weakness will differ depending on the muscle, it is important for clinicians to take this discrepancy into consideration. II.

Mechanisms of muscle weakness in muscular dystrophy

Disruption of dystrophin or the sarcoglycans within the dystrophin protein complex leads to muscular dystrophy. The dystrophin complex is enriched in myofibers and concentrated into costameres, rib-like structures in the plasma membrane. In the absence of dystrophin, the plasma membrane becomes

Disease Severity and Thin Filament Regulation in M9RTPM3Nemaline Myopathy

The mechanism of muscle weakness was investigated in an Australian family with an M9R mutation in TPM3 (alpha-tropomyosin(slow)). Detailed protein analyses of 5 muscle samples from 2 patients showed that nemaline bodies are restricted to atrophied Type 1 (slow) fibers in which the TPM3 gene is expressed. Developmental expression studies showed that alpha-tropomyosin(slow) is not expressed at significant levels until after birth, thereby likely explaining the childhood (rather than congenital) disease onset in TPM3 nemaline myopathy. Isoelectric focusing demonstrated that alpha-tropomyosin(slow) dimers, composed of equal ratios of wild-type and M9R-alpha-tropomyosin(slow), are the dominant tropomyosin species in 3 separate muscle groups from an affected patient. These findings suggest that myopathy-related slow fiber predominance likely contributes to the severity of weakness in TPM3 nemaline myopathy because of increased proportions of fibers that express the mutant protein. Using recombinant proteins and far Western blot, we demonstrated a higher affinity of tropomodulin for alpha-tropomyosin(slow) compared with beta-tropomyosin; the M9R substitution within alpha-tropomyosin(slow) greatly reduced this interaction. Finally, transfection of the M9R mutated and wild-type alpha-tropomyosin(slow) into myoblasts revealed reduced incorporation into stress fibers and disruption of the filamentous actin network by the mutant protein. Collectively, these results provide insights into the clinical features and pathogenesis of M9R-TPM3 nemaline myopathy.

Distribution of muscle weakness in patients with stable chronic obstructive pulmonary disease.

The authors determined the degree of respiratory and peripheral muscle weakness in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Differences in severity of muscle weakness among muscle groups may provide treatment options, such as selective muscle training, to adapt the exercise prescription in pulmonary rehabilitation programs. In addition, this information may add to the knowledge on the mechanisms of muscle weakness. Respiratory and peripheral muscle force were quantified in 22 healthy elderly subjects and 40 consecutive COPD patients (forced expiratory volume in 1 second, percent of predicted value [% pred] 41 +/- 19; transfer factor for carbon monoxide, % pred 47 +/- 26) admitted to a pulmonary rehabilitation program. Lung function, diffusing capacity, isometric force of four peripheral muscle groups (handgrip, elbow flexion, shoulder abduction, and knee extension), neck flexion force, and maximal inspiratory and expiratory pressures were measured. Patients had reduced respiratory muscle strength (mean 64% of control subjects' value [% control]) and peripheral muscle strength (mean 75% control) compared to normal subjects. Inspiratory muscle strength (59 +/- 18% control) was significantly lower than expiratory muscle strength (69 +/- 25% control) and peripheral muscle strength (P < 0.01). Neck flexion force (80 +/- 19% control) was better preserved than maximal inspiratory pressure and shoulder abduction force (70 +/- 15% control, P < 0.01). Handgrip force (78 +/- 16% control) and elbow flexion force (78 +/- 14% control) were significantly less affected than shoulder abduction force (70 +/- 15% control, P < 0.01). Finally, shoulder abduction force and knee-extension force (72 +/- 24% control) were not significantly different. Muscle weakness in stable COPD patients does not affect all muscles to a similar extent. Inspiratory muscle force is affected more than peripheral muscle force, whereas proximal upper limb muscle strength was impaired more than distal upper limb muscle strength.

Metrifonate

Acetylcholinesterase (AChE) inhibitors are currently the most promising drugs available for the treatment of Alzheimer's disease (AD). Their efficacy is based on the cholinergic hypothesis of AD which links reduced levels of cerebral acetylcholine (ACh) with declining cognitive function in affected individuals. AChE inhibitors are believed to work by increasing the level of ACh in the synaptic cleft by binding to local AChE and preventing the hydrolysis of ACh. Metrifonate differs from other AChE inhibitors in that it is a prodrug which is, non-enzymatically converted in vivo to the active moiety 2,2-dichlorovinyl dimethylphosphate (DDVP). DDVP administered alone has a very short plasma elimination half-life, but small amounts released from metrifonate are sufficient to inhibit AChE activity in vivo. DDVP is an irreversible inhibitor of AChE and activity is maintained for several weeks. Metrifonate has been used as an anthelmintic since 1962 and has been under investigation as a treatment for the symptoms of AD since 1990. Randomised, placebo-controlled clinical trials, using a variety of dose regimens, have demonstrated that metrifonate produces a significant, but modest, improvement in the 3 domains of AD: cognition, behaviour and function. However, it should be noted that with some assessment instruments in some trials, the improvement' was actually a reduction in the rate of worsening of symptoms compared with placebo. Weekly and daily schedules, with and without loading doses, have been evaluated and the research supports a fixed daily dose of 40 to 50mg, administered to supply approximately 0.65 mg/kg. In studies of up to 6 months' duration, metrifonate was well tolerated, and adverse events were mild and predominantly gastrointestinal. In clinical practice it is likely that metrifonate will be administered for several years and long term monitoring of adverse events will be important to further define the drug's tolerability profile. Muscle weakness occurred in a dose-related fashion in 20 of 3000 patients taking part in long term trials, and in some patients respiratory support was required. The mechanism of muscle weakness is not well defined and requires further investigation. Conclusions: Clinical data support the use of metrifonate in patients with AD. However, the improvements noted are modest and to date there is no evidence that metrifonate is more effective than other currently approved AChE inhibitors. The unique pharmacokinetic/pharmacodynamic profile of metrifonate may endow the agent with some advantages over other therapies, but this has yet to be evaluated in comparative trials. Moreover, long term studies evaluating the effects of metrifonate on maintenance of independence are required. While the clinical future of metrifonate is uncertain, it is one of a small group of drugs that have been shown to improve the outlook of patients with AD. Metrifonate is administered orally and after absorption is nonenzymatically converted to the active compound 2,2-dichlorovinyl dimethylphosphate (DDVP), at neutral or alkaline pH. After a short reversible phase, DDVP irreversibly binds to acetylcholinesterase (AChE). With the exception of nicotinic receptors, metrifonate does not bind to neurotransmitter receptors or binding sites associated with ion channels. Therefore, the pharmacological action of metrifonate is through inhibition of AChE and a consequent increase in levels of acetylcholine (ACh).

Spontaneous thymoma rat as a model for myasthenic weakness caused by anti‐ryanodine receptor antibodies

The mechanism of muscle weakness in myasthenia gravis and its possible relation to antibodies that are directed against the ryanodine receptor (RyR) were studied by the use of the spontaneous thymoma rat (Buffalo/Mna strain). The present study focused on the motor dysfunction as complicated by impaired subcellular machineries and noted particularly in patients with thymus abnormalities. Rats began to develop skeletal muscle weakness soon after birth and worsened progressively. Rats aged 3 months showed a benign thymoma characterized by proliferative lymphocytes; epithelial cells were stained with anti-RyR peptide antibody. The rat serum contained anti-RyR antibodies, but no anti-acetylcholine receptor antibodies. The electrophysiological study in muscle showed a reduction of contractile force without abnormality in synaptic transmission and membrane properties, suggesting a defect in excitation–contraction coupling. Hypothetically, thymic epithelial cells and skeletal muscles share a common RyR antigen, so that anti-RyR antibodies that target the thymic tissue may react with a homologous target in the muscle. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1655–1660, 1998

Spontaneous thymoma rat as a model for myasthenic weakness caused by anti-ryanodine receptor antibodies.

The mechanism of muscle weakness in myasthenia gravis and its possible relation to antibodies that are directed against the ryanodine receptor (RyR) were studied by the use of the spontaneous thymoma rat (Buffalo/Mna strain). The present study focused on the motor dysfunction as complicated by impaired subcellular machineries and noted particularly in patients with thymus abnormalities. Rats began to develop skeletal muscle weakness soon after birth and worsened progressively. Rats aged 3 months showed a benign thymoma characterized by proliferative lymphocytes; epithelial cells were stained with anti-RyR peptide antibody. The rat serum contained anti-RyR antibodies, but no anti-acetylcholine receptor antibodies. The electrophysiological study in muscle showed a reduction of contractile force without abnormality in synaptic transmission and membrane properties, suggesting a defect in excitation-contraction coupling. Hypothetically, thymic epithelial cells and skeletal muscles share a common RyR antigen, so that anti-RyR antibodies that target the thymic tissue may react with a homologous target in the muscle.