PubMed Health⌕ Search

Biomedical subjects

J A Martyn

Publications and source records attributed to J A Martyn.

At least 19 recordsLinked to original sources
PubMed2001

Long-term denervation impairs insulin receptor substrate-1-mediated insulin signaling in skeletal muscle.

Long-term denervation is associated with insulin resistance. To investigate the molecular bases of insulin resistance, the downstream signaling molecules of insulin receptor including insulin receptor substrate-1 (IRS-1) and phosphatidylinositol 3-kinase (PI 3-K) were examined in skeletal muscle of rats after 7 days of denervation. Long-term denervation attenuated insulin-stimulated activation of the initial steps of the intracellular signaling pathway. Insulin-stimulated tyrosine phosphorylation of insulin receptor was reduced to 36% (P < .005), as was the phosphorylation of IRS-1 to 34% (P < .0001) of control. While insulin receptor protein level was unchanged, the protein expression of IRS-1 was significantly decreased in denervated muscles. Insulin-stimulated percent tyrosine phosphorylation of IRS-1, normalized to the IRS-1 protein expression, was also reduced to 55% (P < .01) of control in denervated muscle. Denervation caused a decline in the insulin-induced binding of p85 regulatory subunit of PI 3-K to IRS-1 to 61% (P < .001) and IRS-1-associated PI 3-K activity to 57% (P < .01). These results provide evidence that long-term denervation results in insulin resistance because of derangements at multiple points, including tyrosine phosphorylation of insulin receptor and its downstream signaling molecule, IRS-1, protein expression of IRS-1, and activation of PI 3-K.

Animals↗
PubMed2001

Pharmacokinetics and pharmacodynamics of vecuronium in children receiving phenytoin or carbamazepine for chronic anticonvulsant therapy.

The pharmacokinetics and time course of action of vecuronium in normal children and children receiving anticonvulsant drugs for prolonged periods were characterized. A bolus dose of vecuronium 0.15 mg kg(-1) was administered i.v. to 10 non-epileptic children and to 10 children on phenytoin and 10 children on carbamazepine, who were matched for age and weight. Plasma concentrations of vecuronium, 3-OH desacetylvecuronium (the primary metabolite of vecuronium) and alpha1-acid glycoprotein (AAG) were determined. Pharmacokinetic variables were derived from plasma samples collected before and after administration of vecuronium. Neuromuscular transmission was monitored by evoked compound electromyography. Recovery of the first twitch of the train-of-four (T1/T0) and the recovery index (RI), the time for 25-75% recovery of T1/T0, were determined. The elimination half-life of vecuronium was significantly reduced in both anticonvulsant groups compared with control [control 48.2 (SD 40.3), phenytoin 23.5 (13.1), carbamazepine 18.4 (16.6) min, P<0.05]. Vecuronium clearance was increased in both anticonvulsant groups [control 9.0 (3.6), phenytoin 15.1 (8.9), carbamazepine 18.8 (13.1) ml kg(-1) min(-1), 0.05<P<0.1]. Children on chronic anticonvulsant therapy had a significantly shorter RI than control [control 21.8 (11), phenytoin 12.5 (8.3), carbamazepine 10.6 (5.9) min, P<0.05]. Concentrations of vecuronium at different degrees of recovery of T1, volumes of distribution and AAG concentrations were not different between groups. Our data confirm anticonvulsant-induced resistance to vecuronium in children and support a pharmacokinetic component contributing to the resistance.

Adolescent↗
PubMed2001

Molecular expression of myostatin and MyoD is greater in double-muscled than normal-muscled cattle fetuses.

Excessive muscling in double-muscled cattle arises from mutations in the myostatin gene, but the role of myostatin in normal muscle development is unclear. The aim of this study was to measure the temporal relationship of myostatin and myogenic regulatory factors during muscle development in normal (NM)- and double-muscled (DM) cattle to determine the timing and possible targets of myostatin action in vivo. Myostatin mRNA peaked at the onset of secondary fiber formation (P < 0.001) and was greater in DM (P < 0.001) than in NM. MyoD expression was also elevated throughout primary and secondary fiber formation (P < 0.001) and greater in DM (P < 0.05). Expression of myogenin peaked later than MyoD (P < 0.05); however, it did not differ between NM and DM. These data show that myostatin and MyoD increase coincidentally during formation of muscle fibers, indicating a coordinated role in the terminal differentiation and/or fusion of myoblasts. Myostatin mRNA is also consistently higher in DM than NM, suggesting that a feedback loop of regulation is also disrupted in the myostatin-deficient condition.

Animals↗
PubMed2000

Nuclear DNA fragmentation and morphological alterations in adult rabbit skeletal muscle after short-term immobilization.

Nuclear DNA fragmentation and ultrastructural changes, indicative of myonuclear apoptosis, were examined in adult skeletal muscle in response to short-term immobilization. Adult rabbits were allocated to 2 days (n=5) or 6 days (n=5) of unilateral casting of the ankle in full plantar flexion or were used as untreated controls (n=2). Atrophy of the soleus muscle was apparent by significant reductions in wet mass of 15% and 26% after 2 days and 6 days of casting (P< or =0.05), respectively. Mean fibre cross-sectional area and myonuclear number per section were also lower (17% and 9.1%, respectively) after 6 days of casting, in comparison with contralateral control muscles (P< or =0.05). Electron-microscopic examination showed condensed chromatin and irregularly shaped myonuclei in muscles immobilized for either 2 days or 6 days. Myofibrillar disruption and abnormalities of the subsarcolemmal mitochondria were also apparent in the absence of inflammation or plasma membrane alterations in cast muscles. Longitudinal and transverse sections showed abundant in situ end-labelling of DNA strand breaks (TUNEL) after 2 days, with less after 6 days, of immobilization. Positive labelling corresponded to myonuclear locations within fibres, yet the number of TUNEL-positive nuclei indicated DNA fragmentation in additional cell types such as capillary endothelial cells or fibroblasts. The data indicate that the immobilization of slow-twitch skeletal muscle in a shortened position rapidly induces morphological alterations consistent with mitochondrial injury and apoptotic myonuclear elimination.

Animals↗
PubMed2000

Onset and duration of action of rocuronium in children receiving chronic anticonvulsant therapy.

The onset and time course of action of rocuronium in normal children and children receiving anticonvulsant drugs for prolonged periods was characterized. A single bolus dose of 0.6 mg.kg-1 rocuronium was administered i.v. to seven nonepileptic patients on no medication, and eight patients on chronic anticonvulsant therapy consisting of either phenytoin, carbamazepine, or both who were age and weight matched. Neuromuscular transmission was monitored by the evoked compound electromyography of the thenar muscles using train of four stimulation every 20 s. Recovery times of the first twitch to 10%, 25%, 50%, 75% and 100% of baseline values and recovery index were obtained. The onset times were 1.05+/-0.5 and 1.41+/-0.5 min for the control and anticonvulsant groups respectively and were not significantly different. Children receiving chronic anticonvulsant therapy had significantly shorter recovery index than the control group (control 10.4+/-5.1 min, anticonvulsant 4.8+/-1.7 min, P<0.05). Furthermore, the duration of recovery to 10%, 50%, 75% and 100% of baseline T1 values was less in the anticonvulsant drug group. Our data confirm resistance to rocuronium in children on chronic anticonvulsant drugs.

Analysis of Variance↗
PubMed2000

Thermal injury induces greater resistance to d-tubocurarine in local rather than in distant muscles in the rat.

UNLABELLED: We tested the hypothesis that resistance to d-tubocurarine (dTC) is more intense in muscles closer to, than distant from, burn, and is related to the expression of immature and total acetylcholine receptors (AChRs). Anesthetized rats received approximately 4% surface area burn over the tibialis muscle of one leg with the contralateral leg serving as control, or approximately 45% of the flank burn, with sham-burned pair fed controls. At 1, 4, 7, or 14 days later, the 50% effective dose of dTC, membrane AChRs, and messenger ribonucleic acid (mRNA) that encode the AChR gamma-subunit (AChRgamma-mRNA) were quantified in the tibialis. After the local leg burn, AChRs increased at Days 4, 7, and 14, and AChRgamma-mRNA at Days 4 and 7 after burn. The increased AChRgamma-mRNA correlated with total AChRs (r = 0.82), suggesting that the up-regulated AChRs may contain the immature isoform. The 50% effective dose of dTC after the local leg burn increased 1.2- to 1.5-fold at all periods and correlated significantly with AChRs (r = 0.54) and AChRgamma-mRNA (r = 0.57). After the flank burn, resistance was seen at Day 14 in association with muscle atrophy; AChRs and AChRgamma-mRNA were unaltered. The resistance to dTC after a local burn occurs sooner, is more marked, and is probably related to both increases and isoform changes in AChRs. The resistance at distant muscles appears unrelated to AChR changes. IMPLICATIONS: The resistance to d-tubocurarine after a burn differs between muscles near and distant from the burn and seems to depend on quantitative and qualitative changes in acetylcholine receptors and muscle atrophy associated with the insult.

Animals↗
PubMed2000

Neuromuscular effects of mivacurium in 2- to 12-yr-old children with burn injury.

BACKGROUND: Burned patients are usually resistant to the neuromuscular effects of nondepolarizing relaxants, mostly because of receptor changes. The magnitude of the resistance is related to burn size and time after burn. Mivacurium is a muscle relaxant, degraded by plasma cholinesterase, whose enzyme activity is decreased in burns. The present study tested the hypothesis that burn-induced depressed plasma cholinesterase activity counteracts the receptor-mediated resistance, resulting in a lack of resistance to mivacurium. METHODS: Burned patients (n = 23), aged 2-12 yr, subclassified into burns of 10-30% or > 30% of body surface, were studied at < or = 6 days and again at 1-12 weeks after burn if possible. Thirteen additional patients served as controls. Neuromuscular variables monitored included onset and recovery following bolus dose, continuous infusion rates required to maintain 95 +/- 4% paralysis, and recovery rates following infusion. RESULTS: The onset times of maximal twitch suppression were not different between burns and controls, but recovery to 25% of baseline twitch height was prolonged in patients with > 30% burn irrespective of time after injury. The continuous infusion rates to maintain twitch suppression at 95 +/- 4% were not different between groups. The recovery indices, including train-of-four to > 75%, 25-75%, or 5-95% in burned patients, were similar or prolonged compared with controls. The prolonged recovery in burned patients was inversely related to plasma cholinesterase activity (R2 = 0.86, r = -0.93, P < 0.001), and the decreased plasma cholinesterase activity was related to burn size and time after burn. CONCLUSIONS: A normal mivacurium dosage (0.2 mg/kg) effects good relaxation conditions in burned patients, with an onset time similar to that in controls. This finding contrasts with the response seen with other nondepolarizing drugs, higher doses of which are required to effect paralysis. The decreased metabolism of mivacurium, resulting from depressed plasma cholinesterase activity, probably counteracts the receptor-mediated potential for resistance. Because succinylcholine is contraindicated in burned patients, larger doses of nondepolarizing agents are advocated to effect rapid onset of paralysis. This generalization does not hold for mivacurium. diatrics; plasma cholinesterase; relaxant resistance; succinylcholine, alternative to.)

Body Weight↗
PubMed2000

Skeletal muscle apoptosis after burns is associated with activation of proapoptotic signals.

Critical illness is associated with muscle wasting and muscle weakness. Using burn injury as a model of local and systemic inflammatory response, we tested the hypothesis that thermal injury causes apoptosis in muscle. After a 40% body surface area burn to rats, abdominal muscles beneath the burn and limb muscles distant from the burn were examined for apoptosis at varying times after burn. Ladder assay, ELISA, and histological methods showed evidence of apoptosis in the abdominal muscles within 4-12 h with peak changes occurring at 3-7 days. Maximal apoptosis was also evident at distant limb muscles at 3-7 days. Investigation of proapoptotic pathways indicated mitochondrial membrane potential to be altered by 1 h after burn. Starting at 15 min after burn, cytochrome c was released from the mitochondria into the cytosol, followed by increased activity of caspase-3, starting at 6 h after burn. These studies suggest that mitochondria and caspase-mediated apoptotic pathways may be an additional mechanism of muscle weight loss in burns and may be potential therapeutic targets for prevention of muscle wasting.

Abdominal Muscles↗
PubMed2000

Immobilization depresses insulin signaling in skeletal muscle.

Prolonged immobilization depresses insulin-induced glucose transport in skeletal muscle and leads to a catabolic state in the affected areas, with resultant muscle wasting. To elucidate the altered intracellular mechanisms involved in the insulin resistance, we examined insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit (IR-beta) and insulin receptor substrate (IRS)-1 and activation of its further downstream molecule, phosphatidylinositol 3-kinase (PI 3-K), after unilateral hindlimb immobilization in the rat. The contralateral hindlimb served as control. After 7 days of immobilization of the rat, insulin was injected into the portal vein, and tibialis anterior muscles on both sides were extracted. Immobilization reduced insulin-stimulated tyrosine phosphorylation of IR-beta and IRS-1. Insulin-stimulated binding of IRS-1 to p85, the regulatory subunit of PI 3-K, and IRS-1-associated PI 3-K activity were also decreased in the immobilized hindlimb. Although IR-beta and p85 protein levels were unchanged, IRS-1 protein expression was downregulated by immobilization. Thus prolonged immobilization may cause depression of insulin-stimulated glucose transport in skeletal muscle by altering insulin action at multiple points, including the tyrosine phosphorylation, protein expression, and activation of essential components of insulin signaling pathways.

Animals↗
PubMed1999

Fiber atrophy, but not changes in acetylcholine receptor expression, contributes to the muscle dysfunction after immobilization.

OBJECTIVES: Muscle weakness associated with critical illness can be due to the illness itself, immobilization associated with it, and/or to concomitant use of drugs that affect neuromuscular transmission. This study investigated the contribution of immobilization per se to the muscle dysfunction, as well as the associated morphologic and biochemical changes. DESIGN: Prospective, laboratory study. SETTING: Hospital research laboratory. SUBJECTS: Adult, male, Sprague-Dawley rats, weighing 200 to 250 g, were randomly allocated to three experimental groups, depending on the duration (7, 14, or 28 days) of limb immobilization (n = 9 to 11 per group) or sham immobilization (n = 5 to 6 per group). INTERVENTIONS: Chronic, unilateral immobilization (disuse) of the tibialis cranialis muscle was produced by fixing the knee and ankle joints at 90 degrees flexion. The contralateral unimmobilized leg and a separate group of sham-immobilized legs served as controls. MEASUREMENTS AND MAIN RESULTS: After 7, 14, or 28 days of disuse of the tibialis muscles, the peak isometric twitch (Pt) and tetanic (Po) tensions, as well as fatigability during 5 secs of nerve stimulation at 50, 100, and 150 Hz, were measured simultaneously in situ in the immobilized group and in its contralateral control, and in the sham-immobilized group and in its contralateral control. Muscle fiber and endplate morphologies were determined by histochemical methods; membrane acetylcholine receptors (AChRs) were determined by 125I alpha-bungarotoxin assay; and the level of expression of AChR subunit transcripts was determined by reverse transcriptase-polymerase chain reaction. Immobilization reduced Pt, Po, fatigability, muscle mass, and fiber cross-sectional area (p<.001 vs. controls), but did not decrease tension per unit muscle mass, fiber oxidative capacity, or motor endplate size. Muscle mass correlated with fiber cross-sectional area. Changes in fiber cross-sectional area accounted for 23% and 46% (p< or =.043) of the variability in Pt and Po, respectively. Pt and Po correlated poorly with total AChR protein and expression of epsilon- and gamma-subunit messenger RNA. CONCLUSION: To the extent that the immobilization model simulates the disuse-induced muscle dysfunction of critical illness, the results suggest that disuse per se may contribute to the muscle weakness, and that the muscle weakness is explained, almost exclusively, by the fiber atrophy and not by the qualitative or quantitative changes in AChR expression.

Analysis of Variance↗
PubMed1999

A unique mechanism of desensitization to lipolysis mediated by beta(3)-adrenoceptor in rats with thermal injury.

Thermal injury causes a hypermetabolic state associated with increased levels of catabolic hormones, but the molecular bases for the metabolic abnormalities are poorly understood. We investigated the lipolytic responses after beta(3)-adrenoceptor (beta(3)-AR) agonists and evaluated the associated changes in beta-AR and its downstream signaling molecules in adipocytes isolated from rats with thermal injury. Maximal lipolytic responses to a specific beta(3)-AR agonist, BRL-37344, were significantly attenuated at post burn days (PBD) 3 and 7. Despite significant reduction of the cell surface beta(3)-AR number and its mRNA at PBD 3 and 7, BRL-37344 and forskolin-stimulated cAMP levels were not decreased. Glycerol production in response to dibutyryl cAMP, a direct stimulant of hormone-sensitive lipase (HSL) via protein kinase A (PKA), was significantly attenuated. Although immunoblot analysis indicated no differences in the expression and activity of PKA or in the expression of HSL, HSL activity showed significant reductions. Finally, beta(3)-AR-induced insulin secretion was indeed attenuated in vivo. These studies indicate that the beta(3)-AR system is desensitized after burns, both in the adipocytes and in beta(3)-AR-induced secretion of insulin. Furthermore, these data suggest a complex and unique mechanism underlying the altered signaling of lipolysis at the level of HSL in animals after burns.

Adipocytes↗
PubMed1999

Nutritional regulation of IGF-II, but not IGF-I, is age dependent in sheep.

In post-natal animals, plasma concentrations of IGF-I are tightly regulated by nutritional status. The current study reports that plasma levels of IGF-II in sheep are also regulated by nutrition, but whether plasma IGF-II is increased, decreased or remains the same, depends on the age of the animal. Ewe lambs, ranging in age from 2 days to 2 years, were fed or fasted for lengths of time between 24 and 72 h. Blood samples were taken at intervals of 24 h throughout the treatment period and immediately before slaughter. Plasma concentrations of IGF-I increased with advancing age in fed animals (P<0.001) and were reduced by fasting in all age groups (P<0.001). Plasma concentrations of IGF-II also increased as animals matured (P<0.001), but did not show an overall effect of the fasting treatment. An interaction between age and nutrition (P<0.001) resulted from a decrease in plasma IGF-II in response to fasting in neonatal animals (P<0.01) and, conversely, increased levels of plasma IGF-II in fasted mature animals (P<0.01 or P<0.001). Fasted sheep of peripubertal age showed no change in plasma levels of IGF-II. The nutritional sensitivity of serum IGF-binding proteins (BPs) also changed with age. The 29 kDa BP, which we presume to be BP1, was elevated by fasting in young animals and reduced slightly in older animals. BP2 was increased to a similar magnitude by fasting at all ages. BP3 was depressed by fasting in young animals and showed little change in adults. In contrast, a 24 kDa BP, which is probably BP4, showed little change in young animals and was reduced substantially in older sheep. In conclusion, the response of plasma IGF-II to fasting suggests that this peptide has functions in mediating nutritional stress which depend on the age of the animal, and also that the role of IGF-II may differ from that of IGF-I in adults.

Age Factors↗
PubMed1997

Analysis of thermal injury-induced insulin resistance in rodents. Implication of postreceptor mechanisms.

Burn injury is associated with insulin resistance. The molecular basis of this resistance was investigated by examining insulin receptor signaling in rats after thermal injury. The impaired insulin-stimulated transport of [3H]2-deoxyglucose into soleus muscle strips confirmed the insulin resistance following burns. In vivo insulin-stimulated phosphoinositide 3-kinase activity, pivotal in translocation of GLUT4, was decreased in burns when assessed by its insulin receptor substrate-1 (IRS-1)-associated activity. Insulin-induced tyrosine kinase activity of insulin receptor (IR) and tyrosine phosphorylation of IRS-1 were also attenuated. Immunoprecipitated IR, however, appeared to have normal insulin-responsive kinase activity. Finally, immunoprecipitated IRS-1 was tested for its effect on partially purified recombinant IR and was found to inhibit its kinase activity. This inhibitory effect of IRS-1 was abolished by prior treatment of IRS-1 with alkaline phosphatase, indicating that burn injury-related hyperphosphorylation of IRS-1 is similar to that observed in TNFalpha-induced inhibition of IR signaling. All of these changes were observed in the absence of quantitative changes in IR, IRS-1, and phosphoinositide 3-kinase. Alterations in postreceptor insulin signaling, therefore, may be responsible for the insulin resistance after thermal injury.

Alkaline Phosphatase↗
PubMed1997

Regulation by nutrition and age of insulin-like growth factor binding sites in ovine kidney.

The insulin-like growth factors (IGFs) are considered to have a role in the regulation of renal growth and development. The purpose of the present study was to evaluate the effect of nutritional stress on IGF binding in ovine kidney at different postnatal ages. Binding of IGF-I and IGF-II to kidneys of fed and fasted sheep was characterised using histological autoradiography, competitive binding assays, and SDS-PAGE. Nutritional regulation of IGF-I binding was restricted to cells of the proximal tubules of two and 14-day-old lambs where we identified an IGF binding protein which was upregulated in response to fasting and where IGF-II binding was also slightly enhanced. Ontogenetic changes occurred in the glomeruli where IGF-I binding peaked at 6 months (P < or = 0.001), and IGF-II binding increased to 4 months and then plateaued (P < or = 0.01). In the medulla, IGF-II binding was highest at 4 and 6 months (P < or = 0.05). From these studies, we conclude that the IGF axis may play a role in the regulation of the metabolic response to fasting in the kidney of young lambs. Furthermore, the changes with age which are described may reflect a transition period at 4-6 months, from an initial promotion of kidney growth and development in young lambs to establishment of the metabolic and clearance functions in the adult animal.

Aging↗
PubMed1997

Potentiation of mivacurium by rocuronium is age- and time-dependent: a study in children, adolescents, and young and elderly adults.

Potentiation occurs when the steroidal muscle relaxant, rocuronium, is coadministered with the benzylisoquinolinium relaxant, mivacurium. The effect of time and age on this interaction was evaluated in four predetermined groups: children, adolescents, young adults, and elderly adults (15 per group) by monitoring the ulnar nerve-evoked force of contraction of the adductor pollicis (twitch response). During recovery from paralysis induced by 800 micrograms/kg of rocuronium, an infusion of mivacurium was started and maintained for at least 90 minutes to retain the twitch response at 1% to 9% of baseline tension (95 +/- 4% paralysis). Rocuronium at 600 micrograms/kg induced greater than 95% paralysis in 57 of the 60 patients within 2.2 +/- 0.4 (mean +/- SE) minutes. The period of recovery from rocuronium-induced paralysis to 5% of baseline twitch height was longest in the elderly (30.1 +/- 2.9 minutes) and shortest in the adolescents (16.5 +/- 2.4 minutes). The mivacurium infusion requirements to maintain 95 +/- 4% paralysis was highest in children and progressively increased with time. In young and elderly adults, the infusion rates remained lower than that of children and did not change with time. The incidence of satisfactory spontaneous recovery within 20 minutes (train-of-four ratio > 75%) was the highest in children, followed by adolescents and young adults, and was least in the elderly. The residual neuromuscular effect of rocuronium on the subsequent mivacurium infusion was most pronounced in the elderly, followed by young adults, then adolescents, and was least in children.

Adolescent↗
PubMed1997

Na+ channel and acetylcholine receptor changes in muscle at sites distant from burns do not simulate denervation.

Muscle weakness and aberrant responses to neuromuscular relaxants after burn injury are associated with upregulation of acetylcholine receptors (AChRs). Typically, these functional, pharmacological, and biochemical changes occur after denervation, in which transcriptionally mediated qualitative changes in AChRs and Na+ channels and of myogenic regulatory proteins MyoD and myogenin also occur. This study in rats, by an examination of changes in the above-enumerated proteins or their transcripts in the gastrocnemius muscle distant from the burn, verifies whether a denervation-like state exists after burns. Scatchard analysis of [3H]saxitoxin binding revealed no changes in the affinity (K(d)) and total number (B(max)) of Na+ channels between control and burn-injured animals at both 7 and 14 days after injury. The mRNA levels of the immature proteins, SkM2 of the Na+ channels and the gamma-subunits of AChRs, the increase of which is pathognomic of denervation, were assessed by Northern analysis and were unchanged. The transcripts of mature Na+ channels, SkM1, were significantly increased at day 14 after the burn (1.24 +/- 0.10 in burn-injured vs. 1.06 +/- 0.12 in sham animals, arbitrary units, P = 0.006). Although MyoD levels were increased in burn-injured animals at 14 days (0.21 +/- 0.02 vs. 0.15 +/- 0.07 arbitrary units, P = 0.05), myogenin levels were unaltered. The absence of changes in AChR transcripts, including alpha-, delta-, and gamma-subunits, indicates that the upregulation of AChR in burns is not transcriptionally mediated. The unaltered levels of transcripts of myogenin, SkM2 of Na+ channels and gamma-subunit of AChR, confirm that there is no denervation-like prejunctional (nerve-related) component to explain the muscle weakness or the upregulation of AChRs at sites distant from burns.

Animals↗
PubMed1997

Mechanisms for the paradoxical resistance to d-tubocurarine during immobilization-induced muscle atrophy.

This study investigated whether immobilization-induced hyposensitivity to d-tubocurarine (dTC), up-regulation of acetylcholine receptors (AChRs) and changes in fiber size and motor endplate size persist indefinitely and whether they are causally related. Unilateral disuse of the tibialis muscle was produced in adult rats by pinning the knee and ankle joints at 90 degrees flexion. The contralateral unpinned and a separate group of sham-pinned legs served as controls. After 7, 14 or 28 days of disuse, the in vivo dose of dTC that produced 50% depression of nerve-evoked twitch (ED50) in the tibialis muscle increased 3.0-, 3. 2- and 2.1-fold (P < .05), and membrane AChRs increased 6.0- (P < . 05), 6.3- (P > .05) and 1.2-fold (P > .395) relative to control, respectively. Disuse caused muscle fiber atrophy (P < .01) but did not affect endplate size. Hence, the ratio of endplate size to fiber size increased. There was a transient increase in gene expression of all (including de novo expression of the gamma) subunits of the AChR, peaking at day 7 and returning to normal by day 28 of immobilization. The ED50 of dTC correlated directly with AChRs (R2 = 0.51; P < .0001) or the ratio of endplate size to fiber size (R2 = 0. 30; P < .001), and inversely with fiber size (R2 = 0.43, P < .0001). It is proposed that acting together, but not singly, the changes in AChRs, fiber size and relative endplate size contribute to the magnitude and time course of the resistance to dTC produced by chronic disuse.

Animals↗