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The identification of subcellular fluxes of exchange of ATP, phosphocreatine (PCr) and Pi between mitochondria, cytosol and ATPases and pathways of energy transfer in a whole organ is a challenge specially in the myocardium where 50% of creatine kinases (CK) are found in close vicinity of ATP producing (mito-CK) and utilizing (MM-bound CK) reactions. To dissect their contribution in cardiac energy transfer we recently developed a new experimental 31P NMR spectroscopy approach. This led to identify three kinetically different subcellular CKs and to evidence experimentally the CK shuttle in a rat heart perfused in isovolumy. Here we show that a decreased energy demand alters energetic pathways : two CKs (cytosolic and MM-bound) functioning at equilibrium and a non mitochondrial ATP<-->Pi exchange was sufficient to describe NMR data. Mito-CK fluxes was not detected anymore. This confirms the dependence of energy pathways upon cardiac activity. Indeed the subcellular localization and activity of CKs may have important bioenergetic consequences for the in vivo control of respiration at high work: free ADP estimated from global CK equilibrium might not always adequately reflect its concentration at the ANT.
Mol Biol Rep 2002
PMID:Identification of subcellular energy fluxes by P NMR spectroscopy in the perfused heart: contractility induced modifications of energy transfer pathways. 1224 Oct 52

Different tendons are (i) subject to very different stresses from their muscles and (ii) differ in their susceptibility to fatigue damage. The fatigue quality of each tendon is matched to the stress it experiences, so that, in life, all tendons are similarly prone to damage. On-going damage must be routinely repaired to maintain homeostasis and prevent damage from becoming symptomatic. The discovery of major differences in fatigue quality among tendons, which had previously seemed fairly similar in their mechanical properties, raises a wide range of new questions. (A) What structural and chemical differences underlie the variations in fatigue quality? (B) What molecular structure in the tendon is damaged and how is repair organised? (C) Is fatigue quality adaptable and if so what is the trigger for adaptation? Putting these questions into context leads to an integrated review of tendon, including structure and chemistry, the turnover of proteins, the cross-linking of collagen and the response of tenocytes to load on the tendon.
Comp Biochem Physiol A Mol Integr Physiol 2002 Dec
PMID:The implications of the adaptable fatigue quality of tendons for their construction, repair and function. 1248 88

Strain-induced tendinopathy is a common injury in both human and equine athletes, with increasing incidence associated with greater involvement in sport and an increasingly aged population. This paper reviews our studies on the abundant non-collagenous protein, cartilage oligomeric matrix protein (COMP), in equine tendons. Its variation between tendon type and site, age and exercise has provided an insight into how age and exercise influence tendon growth and maturation. Tendons can be broadly divided into two types, reflecting their different matrix composition and function: the energy-storing tendons used for weight-bearing and locomotion, which suffer a high incidence of strain-induced tendinopathy, and positional tendons involved in limb placement or manipulative skills. It would appear that while energy-storing tendon can respond to the mechanical forces applied to it during growth, there is no evidence that it can do so after skeletal maturity. Instead, cumulative fatigue damage causes degeneration at the molecular level, potentially weakening it and increasing the risk of clinical injury. Appropriate exercise regimes early in life may help to improve the quality of growing tendon, thereby reducing the incidence of injury during ageing or subsequent athletic career.
Comp Biochem Physiol A Mol Integr Physiol 2002 Dec
PMID:The influence of ageing and exercise on tendon growth and degeneration--hypotheses for the initiation and prevention of strain-induced tendinopathies. 1248 91

The linear organization of collagen fibers in tendons results in optimal stiffness and strength at low strains under tensile load. However, this organization makes repairing ruptured or lacerated tendons extremely difficult. Current suturing techniques to join split ends of tendons, while providing sufficient mechanical strength to prevent gapping, are inadequate to carry normal loads. Immobilization protocols necessary to restore tendon congruity result in scar formation at the repair site and peripheral adhesions that limit excursion. These problems are reviewed to emphasize the need for novel approaches to tendon repair, one of which is the development of biomimetic tendons. The objective of the empirical work described here was to produce biologically-based, biocompatible tendon replacements with appropriate mechanical properties to enable immediate mobilization following surgical repair. Nor-dihydroguaiaretic acid (NDGA), a di-catechol from creosote bush, caused a dose dependent increase in the material properties of reconstituted collagen fibers, achieving a 100-fold increase in strength and stiffness over untreated fibers. The maximum tensile strength of the optimized NDGA treated fibers averaged 90 MPa; the elastic modulus of these fibers averaged 580 MPa. These properties were independent of strain rates ranging from 0.60 to 600 mm/min. Fatigue tests established that neither strength nor stiffness were affected after 80 k cycles at 5% strain. Treated fibers were not cytotoxic to tendon fibroblasts. Fibroblasts attached and proliferated on NDGA treated collagen normally. NDGA-fibers did not elicit a foreign body response nor did they stimulate an immune reaction during six weeks in vivo. The fibers survived 6 weeks with little evidence of fragmentation or degradation. The polymerization scheme described here produces a fiber-reinforced NDGA-polymer with mechanical properties approaching an elastic solid. The strength, stiffness and fatigue properties of the NDGA-treated fibers are comparable to those of tendon. These fibers are biocompatible with tendon fibroblasts and elicit little rejection or antigenic response in vivo. These results indicate that NDGA polymerization may provide a viable approach for producing collagenous materials that can be used to bridge gaps in ruptured or lacerated tendons. The tendon-like properties of the NDGA-fiber would allow early mobilization after surgical repair. We predict that timely loading of parted tendons joined by this novel biomaterial will enhance mechanically driven production of neo-tendon by the colonizing fibroblasts and result in superior repair and rapid return to normal properties.
Comp Biochem Physiol A Mol Integr Physiol 2002 Dec
PMID:Biomimetic approaches to tendon repair. 1248 99

Cachexia is a common manifestation of late stage malignancy and is characterized by anemia, anorexia, muscle wasting, loss of adipose tissue, and fatigue. Although cachexia is disabling and can diminish the life expectancy of cancer patients, there are still no effective therapies for this condition. We have examined the feasibility of using a myogenic plasmid to express growth hormone-releasing hormone (GHRH) in severely debilitated companion dogs with naturally occurring tumors. At a median of 16 days after intramuscular delivery of the plasmid, serum concentrations of insulin-like growth factor I (IGF-I), a measure of GHRH activity, were increased in 12 of 16 dogs (P < 0.01). These increases ranged from 21 to 120% (median, 49%) of the pretreatment values and were generally sustained or higher on the final evaluation. Anemia resolved posttreatment, as indicated by significant increases in mean red blood cell count, hematocrit, and hemoglobin concentrations, and there was also a significant rise in the percentage of circulating lymphocytes. Treated dogs maintained their weights over the 56-day study and did not show any adverse effects from the GHRH gene transfer. We conclude that intramuscular injection of a GHRH-expressing plasmid is both safe and capable of stimulating the release of growth hormone and IGF-I in large animals. The observed anabolic responses to a single dose of this therapy might be beneficial in patients with cancer-associated anemia and cachexia.
Mol Ther 2002 Dec
PMID:Effects of plasmid-mediated growth hormone-releasing hormone in severely debilitated dogs with cancer. 1249 79

The pathogenesis of neurological sequelae in glutaric aciduria I (GA I) is still unclear. Some evidence exists for compromised energy generation in the brain of patients with GA I resulting in 'slow-onset' excitotoxicity. Previously, we have shown a reduced activity of the mitochondrial ATPsynthase in cultured mixed cortex cells from neonatal rats incubated with 2-4mM 3-hydroxyglutarate (3-OH glut) for 24h. In the present study we measured cellular contents of high energy phosphate compounds (creatinephosphate CP, ATP, and ADP) in this model after a 24h incubation period with 2-4mM glutarate (glut) or 3-OH glut. 3-OH glut specifically led to a reduction of CP content in a dose-dependent manner, whereas concentrations of ATP, ADP, and AMP remained unchanged. The drop in CP-concentration could be prevented by preincubation with the non-competitive NMDA-receptor antagonist MK 801 or coincubation with 1mM creatine. NMDA-receptor associated ion channels may be opened due to a lack of energy inside the neurons caused by a reduction of CP. This is followed by membrane depolarization which could impair electrogenic creatine transport into the cell.
Mol Genet Metab 2003 Feb
PMID:Glutaric aciduria I: creatine supplementation restores creatinephosphate levels in mixed cortex cells from rat incubated with 3-hydroxyglutarate. 1261 82

Scoliosis, a lateral deviation of the spine frequently associated with rotation, is not a specific disease but a deformity complicating many diseases. Curve progression is the major concern irrespective of the initiating cause. Idiopathic scoliosis is arguably postural in nature and in some subjects develops from intrauterine compression. Analysis of the pathogenesis leads to the conclusion that progression is due to an accelerated premature osteoarthrosis induced by insidious tissue fatigue of biomechanical origin. The chronic cumulative effect of repetitive tensile stresses applied asymmetrically to the postural deformity, manifested by loss of tensile strength and tissue cohesion, leads to fragility and eventual tissue disintegration of vertebrae, intervertebral discs, and laxity of ligaments. Early treatment, prevention, and avoidance of stresses that accentuate progression are of paramount import.
Exp Mol Pathol 2003 Feb
PMID:Pathogenesis of idiopathic scoliosis revisited. 1264 32

A human MusTRD (muscle TFII-I repeat domain (RD)-containing protein) isoform was originally identified in a yeast one-hybrid screen as a protein that binds the slow fibre-specific enhancer of the muscle gene troponin I slow [O'Mahoney, Guven, Lin, Joya, Robinson, Wade and Hardeman (1998) Mol. Cell. Biol. 18, 6641-6652]. MusTRD shares homology with the general transcription factor TFII-I by the presence of diagnostic I-RDs [Roy (2001) Gene 274, 1-13]. The human gene encoding MusTRD, GTF2IRD1 ( WBSCR11 / GTF3 ), was subsequently located on chromosome 7q11.23, a region deleted in the neurodegenerative disease, Williams-Beuren Syndrome [Osborne, Campbell, Daradich, Scherer, Tsui, Franke, Peoples, Francke, Voit, Kramer et al. (1999) Genomics 57, 279-284; Franke, Peoples and Francke (1999) Cytogenet. Cell. Genet. 86, 296-304; Tassabehji, Carette, Wilmot, Donnai, Read and Metcalfe (1999) Eur. J. Hum. Genet. 7, 737-747]. The haploinsufficiency of MusTRD has been implicated in the myopathic aspect of this disease, which manifests itself in symptoms such as lowered resistance to fatigue, kyphoscoliosis, an abnormal gait and joint contractures [Tassabehji, Carette, Wilmot, Donnai, Read and Metcalfe (1999) Eur. J. Hum. Genet. 7, 737-747]. Here, we report the identification of 11 isoforms of MusTRD in mouse skeletal muscles. These isoforms were isolated from a mouse skeletal muscle cDNA library and reverse transcription-PCR on RNA from various adult and embryonic muscles. The variability in these isoforms arises from alternative splicing of a combination of four cassettes and two mutually exclusive exons, all in the 3' region of the primary transcript of Gtf2ird1, the homologous mouse gene. The expression of some of these isoforms is differentially regulated spatially, suggesting individual regulation of the expression of these isoforms. Co-transfection studies in C2C12 muscle cell cultures reveal that isoforms differentially regulate muscle fibre-type-specific promoters. This indicates that the presence of different domains of MusTRD influences the activity exerted by this molecule on multiple promoters active in skeletal muscle.
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PMID:Regulation of alternative splicing of Gtf2ird1 and its impact on slow muscle promoter activity. 1278 Mar 50

For a young scoliotic boy the customary "wait and watch" management program for rapidly progressive juvenile idiopathic scoliosis was considered unsatisfactory in view of the poor prognosis. The management program devised was based on the congenital postural induction concept of scoliosis with progression accruing from mechanically induced bioengineering fatigue, cumulative molecular scissions, laxity of ligaments, and secondary bone deformation. A coexisting pelvic tilt with restricted movement of the hip and shoulder joints was overlooked initially. Possibly induced simultaneously with the scoliosis, it is considered a contributory factor in scoliosis progression and requires early diagnosis and correction. The rapid improvement in this child's spinal status achieved by physiological traction and specifically designed exercises was such that as a preventive measure the technique warrants further clinical assessment on young scoliotics.
Exp Mol Pathol 2003 Jun
PMID:Regression of juvenile idiopathic scoliosis. 1278 22

In most tissues the mitochondrial ATP-synthase plays a central role by synthesizing the bulk of ATP. According to the classical theory of respiratory control, flux through this enzyme is solely determined by substrate (ADP) concentration while the enzyme has a fixed capacity. However, in different cell types such as rat cardiomyocytes and neurons, dog heart, human fibroblasts, and skeletal and heart muscle from children, it has been shown that active regulation of the mitochondrial ATP-synthase in response to cellular energy demand exists. For example, in rat cardiomyocytes the mitochondrial ATP-synthase activity is down-regulated in response to anoxia or mitochondrial uncoupling. By this mechanism cellular ATP is conserved, as under these conditions the ATP-synthase would work in reverse and hydrolyze ATP. When cardiomyocytes are stimulated to contract, ATP-synthase activity is up-regulated in line with the increased energy demand. Preincubation of the cardiomyocytes with positive inotropic substances results in further up-regulation of the ATP-synthase. By blocking calcium transport, it has been shown that the up-regulation of the enzyme is calcium-dependent. On a molecular level, up-regulation is probably mediated by the calcium-binding inhibitor protein (CaBI) and down-regulation via the inhibitor protein IF(1). The ATP-synthase system is disturbed under several pathophysiological conditions. First, mutations can cause a primary defect in the mitochondrial ATP-synthase (respiratory chain defect). Furthermore, secondary defects of the ATP-synthase occur. In rat models abnormalities of ATP-synthase can be detected in different types of cardiomyopathy/heart hypertrophy. The changes are reversible in response to treatment of the heart diseases. Abnormalities of the ATP-synthase system can be observed in fibroblasts from patients with neuronal ceroidlipofuscinoses. Toxic metabolites accumulating in methylmalonic acidurias can inhibit ATP-synthase. When neurons are incubated with 3-OH glutarate - a substance accumulating in glutaric aciduria I-as a model for glutaric aciduria I, ATP-synthase activity is compromised. This lack of energy may lead to 'slow onset' excitotoxicity and finally cell death. Cells can be rescued by adding creatine to the incubation medium. In D-2-hydroxyglutaric aciduria, inhibition of the ATP-synthase has been observed.
Mol Genet Metab 2003 Jun
PMID:Regulation of the mitochondrial ATP-synthase in health and disease. 1280 36


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