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PubMed2024

The effect of low birth weight as an intrauterine exposure on the early onset of sarcopenia through possible molecular pathways.

Sarcopenia, a musculoskeletal disease characterized by the progressive loss of skeletal muscle mass, strength, and physical performance, presents significant challenges to global public health due to its adverse effects on mobility, morbidity, mortality, and healthcare costs. This comprehensive review explores the intricate connections between sarcopenia and low birth weight (LBW), emphasizing the developmental origins of health and disease (DOHaD) hypothesis, inflammatory processes (inflammaging), mitochondrial dysfunction, circadian rhythm disruptions, epigenetic mechanisms, and genetic variations revealed through genome-wide studies (GWAS). A systematic search strategy was developed using PubMed to identify relevant English-language publications on sarcopenia, LBW, DOHaD, inflammaging, mitochondrial dysfunction, circadian disruption, epigenetic mechanisms, and GWAS. The publications consist of 46.2% reviews, 21.2% cohort studies, 4.8% systematic reviews, 1.9% cross-sectional studies, 13.4% animal studies, 4.8% genome-wide studies, 5.8% epigenome-wide studies, and 1.9% book chapters. The review identified key factors contributing to sarcopenia development, including the DOHaD hypothesis, LBW impact on muscle mass, inflammaging, mitochondrial dysfunction, the influence of clock genes, the role of epigenetic mechanisms, and genetic variations revealed through GWAS. The DOHaD theory suggests that LBW induces epigenetic alterations during foetal development, impacting long-term health outcomes, including the early onset of sarcopenia. LBW correlates with reduced muscle mass, grip strength, and lean body mass in adulthood, increasing the risk of sarcopenia. Chronic inflammation (inflammaging) and mitochondrial dysfunction contribute to sarcopenia, with LBW linked to increased oxidative stress and dysfunction. Disrupted circadian rhythms, regulated by genes such as BMAL1 and CLOCK, are associated with both LBW and sarcopenia, impacting lipid metabolism, muscle mass, and the ageing process. Early-life exposures, including LBW, induce epigenetic modifications like DNA methylation (DNAm) and histone changes, playing a pivotal role in sarcopenia development. Genome-wide studies have identified candidate genes and variants associated with lean body mass, muscle weakness, and sarcopenia, providing insights into genetic factors contributing to the disorder. LBW emerges as a potential early predictor of sarcopenia development, reflecting the impact of intrauterine exposures on long-term health outcomes. Understanding the complex interplay between LBW with inflammaging, mitochondrial dysfunction, circadian disruption, and epigenetic factors is essential for elucidating the pathogenesis of sarcopenia and developing targeted interventions. Future research on GWAS and the underlying mechanisms of LBW-associated sarcopenia is warranted to inform preventive strategies and improve public health outcomes.

Humans↗

PubMed1999

The physiological consequences of bed rest and inactivity.

Most dialysis patients experience prolonged periods of physical inactivity and often bedrest. The physiological consequences of bed rest and inactivity are many and detrimentally affect the functioning of many bodily systems, several of which affect physical functioning. Reductions in plasma volume reduce cardiac filling, stroke volume, and cardiac output. Skeletal muscle fiber size, diameter, and capillarity are reduced, as is bone density. These changes result in profound reductions in physical work capacity. The effects of bed rest and inactivity in patients with chronic renal failure may have more serious consequences, in that they may exacerbate the pathophysiology of renal failure such as cardiac dysfunction, anemia, muscle wasting, muscle weakness, neuropathy, glucose intolerance, and reduced bone density.

Bed Rest↗

PubMed2002

Mitochondrial neurogastrointestinal encephalomyopathy and thymidine metabolism: results and hypotheses.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease with mitochondrial DNA (mtDNA) alterations and is caused by mutations in the nuclear gene encoding thymidine phosphorylase (TP). The cardinal clinical manifestations are ptosis, ophthalmoparesis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy. Skeletal muscle shows mitochondrial abnormalities, including ragged-red fibers and cytochrome c oxidase deficiency, together with mtDNA depletion, multiple deletions or both. In MNGIE patients, TP mutations cause a loss-of-function of the cytosolic enzyme, TP. As a direct consequence of the TP defect, thymidine metabolism is altered. High blood levels of this nucleoside are likely to lead to mtDNA defects even in cells that do not express TP, such as skeletal muscle. We hypothesize that high concentrations of thymidine affect dNTP (deoxyribonucleoside triphosphate) metabolism in mitochondria more than in cytosol or nuclei, because mitochondrial dNTPs depend mainly on the thymidine salvage pathway, whereas nuclear dNTPs depend mostly on de novo pathway. The imbalance in the mitochondrial dNTP homeostasis affects mtDNA replication, leading to mitochondrial dysfunction.

Journal Article↗

PubMed2000

Assessment of facial nerve function in acoustic tumor disease by nasal muscle F waves and transcranial magnetic stimulation.

Standard transcranial magnetic stimulation and nasal muscle F-wave recordings were used to assess proximal facial nerve function in 27 patients with unilateral acoustic tumors (mean diameter, 29 mm) and clinically intact facial nerve function. Latency measurements for F waves and cortical magnetic stimulation were abnormal. Moreover, F ratios, central motor conduction time, and the ratio of response latency to cortical and cisternal magnetic stimulation were significantly increased. Amplitudes were unchanged. Correlation analysis with tumor diameter as dependent variable yielded maximum r values for F-wave latencies (0.57) and F ratios (0.41), whereas for magnetic stimulation, a significant correlation could be found (0.4) only for cortical stimulation. Nasal muscle F-wave recording can reveal clinically inapparent facial nerve dysfunction. Its efficacy in predicting tumor diameter seems to be superior to that of standard magnetic stimulation.

Adult↗

PubMed2000

The split hand in ALS has a cortical basis.

Loss of highly fractionated movement involving the thumb and index finger is an early characteristic of hand dysfunction in many ALS patients. These movements are largely subserved by the 'thenar complex' including the first dorsal interosseus muscle (FDI), whereas the 'hypothenar complex', innervated by the same myotome, has less ability to fractionate and is relatively spared. This suggests that in ALS, hand dysfunction and wasting is related to corticomotoneuronal representation and input. To determine whether corticomotoneuronal input to the thenar spinal pool is preferentially impaired compared to the hypothenar spinal pool in ALS, we studied 18 ALS patients and 11 normal subjects. Compound muscle action potentials (CMAPs) and motor evoked potentials (MEPs) of the thenar and hypothenar complexes were evoked by peripheral nerve stimulation and transcranial magnetic stimulation. In healthy control subjects the cortical/peripheral (MEP/CMAP) ratios were significantly larger for the thenar complex suggesting a stronger corticomotoneuronal input to this muscle complex (P<0.005). This was not the case in ALS patients. Comparing the ratios between control subjects and patients revealed a significant reduction for the thenar complex (P<0.02) in ALS patients but not for the hypothenar complex. We conclude that corticomotoneuronal input to the thenar complex is preferentially affected in ALS and that corticomotoneuronal disease may be the prime determinant of hand dysfunction and wasting.

Amyotrophic Lateral Sclerosis↗

PubMed2001

Back muscle fatigability is associated with knee extensor inhibition in subjects with low back pain.

STUDY DESIGN: Cross-sectional study of 25 male golfers with chronic low back pain and 16 healthy controls of similar age. OBJECTIVES: To assess the association between functional capacity of the back extensors and the quadriceps muscles. SUMMARY OF BACKGROUND DATA: Chronic low back pain has been shown to lead to changes in muscle activation patterns of the abdominals and the gluteus maximus. The effect of chronic low back pain on lower limb function has not been investigated. METHODS: Back extensor endurance was assessed by a Biering-Sørensen test; surface EMG was measured bilaterally on the erector spinae at T12 and L4--L5. Muscle inhibition in the quadriceps was assessed by applying an electrical twitch to the maximally contracted muscle. The associations between holding time, decrease in EMG median frequency (i.e., the slope of the regression line on median frequency vs. time), and muscle inhibition were compared for study participants with chronic low back pain and controls. RESULTS: Mean back extensor holding times were 88 +/- 30 seconds for study participants with chronic low back pain and 92 +/- 17 seconds for controls. Both groups showed bilaterally similar decreases in EMG median frequency at L4--L5 and T12; however, the slopes were significantly steeper at L4--L5 than T12. Study participants with chronic low back pain with poor back endurance had significantly higher muscle inhibition compared with study participants with chronic low back pain with good back endurance, whereas such an association was not evident in healthy controls. CONCLUSIONS: In golfers with chronic low back pain reduced back endurance was associated with significant inhibition of the knee extensors, indicating that this muscle group cannot be activated to a full extent. These findings suggest a possible association between back extensor fatigability and knee extensor dysfunction in male golfers with chronic low back pain.

Adult↗

PubMed2000

Injection of iron compounds followed by induction of the stress response causes tissue injury and apoptosis.

To determine whether iron-laden tissue subsequently stimulated to produce the stress ("heat shock") response-sustained injury, hindlimbs of male ND4 mice were injected with iron salts, hemin, or hemoglobin. The stress response was induced with sodium arsenite or with heat. Ulcers appeared at the injection site. Tissues were analyzed by three distinct techniques-electron microscopy, TUNEL stain, and agarose gel electrophoresis of low molecular weight DNA-which collectively suggest that the tissue injury is, at least in part, the consequence of accelerated apoptosis. The data suggest that the toxicity of free iron is amplified by induction of the stress (heat shock) response to signal a programmed response. This model and mechanism may have implications in pathological processes ranging from the cutaneous wounds of venous stasis disease to the tissue failure of multiple organ dysfunction.

Animals↗

PubMed2005

Enthesitis of biceps brachii short head and coracobrachialis at the coracoid process: a generator of shoulder and neck pain.

This series describes the outcome of diagnostic block at the coracoid process's common origin of the biceps brachii short head and coracobrachialis for anterior shoulder pain and cervical myofascial pain syndrome in six patients. All showed significant tenderness over the tip of the coracoid process. All underwent diagnostic injection with Marcaine at the coracoid process, followed by therapeutic injection with Marcaine and DepoMedrol. All reported complete relief of pain after local injection. Enthesitis at the coracoid process needs to be considered as a causative or contributing factor in patients presenting with shoulder and neck symptoms. No study was found in the literature describing this association. Whether tendonitis of the common origin is a primary cause or result of chronic neck and shoulder dysfunction remains to be established.

Adult↗

PubMed2004

Hereditary neuropathy with liability to pressure palsy: fulminant development with axonal loss during military training.

Hereditary neuropathy with liability to pressure palsy (HNPP) is characterised by recurrent mononeuropathies following minor trauma. We describe a case of fulminant HNPP beginning on the first day of military physical training. Protracted weakness, muscle atrophy, hand contractures, and multifocal sensory loss developed during a further three weeks of basic training. Nerve conduction changes were typical of HNPP, but without segmental slowing. Electromyographically, there was prominent acute denervation in muscles of the hands and right shoulder. Sural nerve biopsy demonstrated tomaculae and remyelination. Genetic testing revealed PMP-22 gene deletion. This case report demonstrates that HNPP can present with rapidly progressive peripheral nerve dysfunction and electrophysiological evidence of focal axonal loss.

Adult↗

PubMed1994

Absence of cytochrome c oxidase activity in a boy with dysfunction of renal tubules, brain and muscle.

We report on a boy who developed proximal renal tubular acidosis with loss of carnitine at the age of about 6 months. A few months later he began to suffer from progressive muscular weakness and neurological disturbances. Blood biochemistry showed elevated lactate and beta-hydroxybutyrate with increased lactate/pyruvate and beta-hydroxybutyrate/acetoacetate ratios. A high urinary excretion of lactate and citric acid cycle intermediates was found. These results indicated a defect of the mitochondrial respiratory chain. Analysis of biopsy material from skeletal muscle revealed low activities of all respiratory chain complexes. In muscle and fibroblasts cytochrome c-oxidase (complex IV) was absent. Despite high dose multi-vitamin therapy the boy died at the age of 30 months from central respiratory failure. At autopsy the neuropathological diagnosis of Leigh disease was made.

Acidosis, Renal Tubular↗

PubMed2002

Mitochondrial DNA depletion in Leigh syndrome.

Leigh syndrome is a heterogenous neurologic disease characterized by seizures, developmental delay, muscle weakness, respiratory abnormalities, optic abnormalities, including atrophy and ophthalmoplegia, and progressive cranial nerve degeneration with early onset in infants and children. Diagnosis can be confirmed by characteristic pathologic findings of necrosis in the basal ganglia, thalamus, and brainstem. Severe dysfunction of mitochondrial energy metabolism is generally present and involved in the etiology of this degenerative central nervous system disease. At the molecular level, a number of point mutations have been located in mitochondrial DNA genes, including ATPase6 and tRNA(Lys) genes, and in nuclear genes encoding subunits of oxidative enzymes, such as pyruvate dehydrogenase. Biochemically these mutations are responsible for enzymatic defects in either respiratory complexes (I, IV, or V) or pyruvate dehydrogenase. We describe here the first case of Leigh syndrome with marked depletion of mitochondrial DNA levels in skeletal muscle and abnormal activities in skeletal muscle of mitochondrial respiratory complexes I, III, IV, and V.

Brain↗

PubMed2006

Complex I deficiency in Persian multiple sclerosis patients.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system characterized by the morphological hallmarks of inflammation, demyelination and axonal loss. Until now, little attention has been paid to the contribution of mitochondrial respiratory chain enzyme activities to MS. In this study, kinetic analysis of mitochondrial respiratory chain complex I enzyme (measured as NADH-ferricyanide reductase) was performed on intact mitochondria isolated from fresh skeletal muscle in MS patients (n = 10) and control subjects (n = 11). Mitochondrial DNA common deletion and deletions were also tested in MS patients. Our findings showed that complex I activities were significantly reduced (P = 0.007) in patients compared with control. However, we could not find deletion in mtDNA of patients with MS. The presupposition of relationship between MS and mitochondrial disorders is due to predominant maternal transmission of MS in affected parent-child pairs, pathoaetiological role of respiratory chain dysfunction in multisystem disorders and important role of it in neurodegenerative disorders, a number of patients such as LHON or other mtDNA abnormality with developed neurological symptoms indistinguishable from MS and similarity of clinical symptoms in mitochondrial disorders to those of MS. This study suggested that a biochemical defect in complex I activity may be involved in pathogenesis of MS.

Adult↗

PubMed2006

The neuroprotective effects of a locally acting IGF-1 isoform.

In the last decade, dramatic progress has been made in elucidating the molecular defects underlying a number of neuromuscular diseases. With the characterization of mutations responsible for muscle and nerve dysfunction in several inherited pathologies, and the identification of novel signaling pathways, in which subtle alterations can lead to significant defects in tissue metabolism, the field is poised to devise successful strategies for treatment of this debilitating and often fatal group of human ailments. Yet progress in therapeutic application has been slow despite our newly gained knowledge of basic biology. Hence, where direct therapeutic approaches to address the primary diseases are still sub-optimal, it may be more effective to focus on strategies for improving neuromuscular function. Among potential candidates, insulin-like growth factor (IGF-1) has been involved in several anabolic pathways in both skeletal muscle and the nervous system and it is a promising candidate to attenuate neuromuscular diseases. In this review, we will discuss the role of IGF-1 isoforms in neuromuscular diseases and the contribution of muscle-produced IGF-1 (mIGF-1) to motor neuron survival and activity.

Animals↗

PubMed1980

N-Acetylglucosamine-asparagine levels in tissues of patients with aspartylglycosaminuria.

The levels of the main glycoprotein-derived storage compound, N-acetylglucosamine-asparagine, in various post mortem tissues of three adult patients with inherited deficiency of lysosomal 1-aspartamido-beta-N-acetylglucosamine amidohydrolase (aspartylglycosaminuria) were measured by gas-liquid chromatography. All aspartylglycosaminuria tissues studied contained significant amounts of N-acetylglucosamine-asparagine, whereas none of the corresponding control tissues contained detectable amounts of this compound. High levels of N-acetylglucosamine-asparagine were found in the liver (3.65 mg/g wet weight), spleen (2.24) and thyroid (2.18), and lower levels in the kidney (0.89), brain (0.53), spinal cord (0.32), sciatic nerve (0.34) and skeletal muscle (0.16). The results show that N-acetylglucosamine-asparagine accumulates chiefly in tissues with important functions in glycoprotein metabolism and/or high endocytic activity. Correlation of the results to the clinical manifestations of aspartylglycosaminuria did not reveal a direct relationship between the amount of N-acetylglucosamine-asparagine stored and the degree of organ dysfunction.

Acetylglucosamine↗

PubMed1987

Gastric and esophageal emptying in dystrophia myotonica. Effect of metoclopramide.

Gastric and esophageal emptying were measured using scintigraphic techniques in 16 patients with dystrophia myotonica and in 22 normal volunteers. Gastric emptying of a solid meal was slower than the normal range (defined as the mean +/- two standard deviations obtained in the normal volunteers) in 15 of the 16 patients, and gastric emptying of the liquid meal was slower than the normal range in 10 of the patients. Esophageal emptying was also markedly delayed in patients, with 15 of 16 patients having an emptying time longer than the normal range. There was no relationship between gastrointestinal symptoms, or the severity of the peripheral (skeletal) muscle weakness, and either gastric or esophageal emptying. Oral administration of metoclopramide resulted in a significant improvement in gastric emptying of the solid meal and a nonsignificant trend toward more rapid liquid emptying, but no change in esophageal emptying. These results indicate that there is a very high prevalence of gastric and esophageal smooth muscle dysfunction in dystrophia myotonica and that gastroparesis is likely to be a treatable cause of morbidity in this disease.

Adult↗

PubMed2003

Clinical utility of the Duncan-Ely test for rectus femoris dysfunction during the swing phase of gait.

The Ely Test (or Duncan-Ely test) has been accepted as a clinical tool to assess rectus femoris spasticity by passively flexing the knee rapidly while the patient lies prone in a relaxed state. In this retrospective review, patients' dynamic knee range of motion (ROM) during gait and an electromyogram (EMG) were compared with the results of the Ely test. Data for 70 patients (44 males, 26 females; 104 limbs) were included. Mean age of patients was 13 years, SD 9 years, range 4 years 5 months to 54 years. All patients were diagnosed with cerebral palsy (spastic diplegia, n = 42; spastic quadriplegia, n = 15, and hemiplegia, n = 13). All patients were ambulatory (50 independent, 20 with assistive devices). A standard matrix was used to calculate sensitivity and specificity of the Ely test as well as its positive and negative predictive value. For the gait variables examined (decreased dynamic knee ROM, timing of peak knee flexion, and abnormal EMG in swing) the sensitivity of the Ely test ranged from 56 to 59% and the specificity ranged from 64 to 85%. For the same variables the positive predictive value ranged from 91 to 98% and the negative predictive value ranged from 4 to 19%. The Ely test was shown to have a good positive predictive value (i.e. the certainty about the presence of rectus spasticity in patients with a positive Ely test result) for rectus femoris dysfunction during gait.

Adolescent↗

PubMed2002

Cardiomyopathy in zebrafish due to mutation in an alternatively spliced exon of titin.

The zebrafish embryo is transparent and can tolerate absence of blood flow because its oxygen is delivered by diffusion rather than by the cardiovascular system. It is therefore possible to attribute cardiac failure directly to particular genes by ruling out the possibility that it is due to a secondary effect of hypoxia. We focus here on pickwickm171 (pikm171), a recessive lethal mutation discovered in a large-scale genetic screen. There are three other alleles in the pik complementation group with this phenotype (pikm242, pikm740, pikm186; ref. 3) and one allele (pikmVO62H) with additional skeletal paralysis. The pik heart develops normally but is poorly contractile from the first beat. Aside from the edema that inevitably accompanies cardiac dysfunction, development is normal during the first three days. We show by positional cloning that the 'causative' mutation is in an alternatively-spliced exon of the gene (ttn) encoding Titin. Titin is the biggest known protein and spans the half-sarcomere from Z-disc to M-line in heart and skeletal muscle. It has been proposed to provide a scaffold for the assembly of thick and thin filaments and to provide elastic recoil engendered by stretch during diastole. We found that nascent myofibrils form in pik mutants, but normal sarcomeres are absent. Mutant cells transplanted to wildtype hearts remain thin and bulge outwards as individual cell aneurysms without affecting nearby wildtype cardiomyocytes, indicating that the contractile deficiency is cell-autonomous. Absence of Titin function thus results in blockage of sarcomere assembly and causes a functional disorder resembling human dilated cardiomyopathies, one form of which is described in another paper in this issue.

Alternative Splicing↗

PubMed1970

Some biochemical effects of triamcinolone acetonide on rat liver and muscle.

1. The powerful anti-inflammatory glucocorticoid triamcinolone acetonide, administered to rats at 20 and 2.5mg/kg, leads to a decrease in the incorporation in vivo of [(3)H]uridine and [(32)P]orthophosphate into hind-limb skeletal muscle. 2. At the higher dose, this decrease in the rate of incorporation of precursors into RNA precedes a decrease in the incorporating ability of muscle ribosomes, which commences about 4-5h after drug administration, but is unaccompanied by any changes in the concentration of tissue ATP or free amino acids. 3. The ribosomal dysfunction extends to polyribosomes, which can only be successfully isolated from the muscle of triamcinolone-treated animals after the addition of alpha-amylase to the tissue homogenate to remove glycogen. 4. The specific radioactivity of muscle protein labelled in vivo with (14)C-labelled amino acids does not decrease progressively after triamcinolone administration. After 2h there is an apparent stimulation of incorporation which leads to an overall discrepancy between measurements of protein-synthetic activity made in vivo and in vitro. 5. There is a significant increase in muscle-glycogen concentration between 8 and 12h after the administration of triamcinolone acetonide (20mg/kg), although a significant decrease occurs after 4h. The fall in glycogen concentration may be due to a decrease in the rate of synthesis of protein essential for glucose uptake into the tissues. 6. As judged by (a) incorporation of (14)C-labelled amino acids into protein, (b) [(3)H]uridine and [(32)P]-orthophosphate incorporation into RNA, (c) the rate of induction of tryptophan pyrrolase and (d) changes in the pool sizes of taurine and tryptophan, the responses in liver followed the same time-course as those in muscle after administration of the drug.

Adenosine Triphosphate↗