Biomedical subjects

G S Lynch

Publications and source records attributed to G S Lynch.

At least 19 recordsLinked to original sources

PubMed2006

Duchenne muscular dystrophy: focus on pharmaceutical and nutritional interventions.

Duchenne muscular dystrophy is a lethal X-linked muscle disease resulting from a defect in the muscle membrane protein dystrophin. The absence of dystrophin leads to muscle membrane fragility, muscle death (necrosis) and eventual replacement of skeletal muscle by fat and fibrous connective tissue. Extensive muscle wasting and respiratory failure results in premature death often by the early 20s. This short review evaluates drug and nutritional interventions designed to reduce the severity of muscular dystrophy, while awaiting the outcome of research into therapies to correct the fundamental gene defect. Combinations of dietary supplementation with amino-acids such as creatine, specific anti-inflammatory drugs and perhaps drugs that target ion channels might have immediate realistic clinical benefits although rigorous research is required to determine optimal combinations of such interventions.

Adrenal Cortex Hormones↗

PubMed2006

Comparative evaluation of IGF-I gene transfer and IGF-I protein administration for enhancing skeletal muscle regeneration after injury.

Developing methodologies to enhance skeletal muscle regeneration and hasten the restoration of muscle function has important implications for minimizing disability after injury and for treating muscle diseases such as Duchenne muscular dystrophy. Although delivery of various growth factors, such as insulin-like growth factor-I (IGF-I), have proved successful in promoting skeletal muscle regeneration after injury, no study has compared the efficacy of different delivery methods directly. We compared the efficacy of systemic delivery of recombinant IGF-I protein via mini-osmotic pump (approximately 1.5 mg/kg/day) with a single electrotransfer-assisted plasmid-based gene transfer, to hasten functional repair of mouse tibialis anterior muscles after myotoxic injury. The relative efficacy of each method was assessed at 7, 21 and 28 days post-injury. Our findings indicate that IGF-I hastened functional recovery, regardless of the route of IGF-I administration. However, gene transfer of IGF-I was superior to systemic protein administration because in the regenerating muscle, this delivery method increased IGF-I levels, activated intracellular signals (Akt phosphorylation), induced a greater magnitude of myofiber hypertrophy and hastened functional recovery at an earlier time point (14 days) after injury than did protein administration (21 days). Thus, the relative efficacy of different modes of delivery is an important consideration when assessing the therapeutic potential of various proteins for treating muscle injuries and skeletal muscle diseases.

Animals↗

PubMed2004

Tackling Australia's future health problems: developing strategies to combat sarcopenia--age-related muscle wasting and weakness.

Some of the most serious consequences of ageing are its effects on skeletal muscle structure and function. Ageing is associated with a progressive loss of muscle mass (sarcopenia), a slowing of movement, and a decline in strength; factors that increase the risk of injury from sudden falls and a reliance on the frail elderly for assistance in accomplishing even the most basic tasks required for independent living. From a public health perspective, sarcopenia has widespread clinical implications. As the proportion of older persons in the population continues to grow, sarcopenia will have a dramatic impact on the lives of Australians and place increasing demands on health care. Although it is generally agreed that the deleterious effects of ageing on skeletal muscle are inevitable, debate exists as to whether these intrinsic changes are immutable or reversible. There is clearly a profound need for therapeutic strategies that can slow the effects of ageing on muscle function, and restore muscle size and strength in the frail elderly so that their quality of life can be maintained or improved. Physical activity plays an important role in slowing the effects of ageing, but exercise alone will not prevent the gradual decline in skeletal muscle function. Other factors, such as age-related changes in circulating levels of muscle anabolic hormones and growth factors, must also be considered when developing strategies to combat sarcopenia. Much research is needed to test the safety and efficacy of these exciting experimental strategies before they can be recommended for clinical application.

Activities of Daily Living↗

PubMed2001

Force and power output of fast and slow skeletal muscles from mdx mice 6-28 months old.

1. Differences in the effect of age on structure-function relationships of limb muscles of mdx (dystrophin null) and control mice have not been resolved. We tested the hypotheses that, compared with limb muscles from age-matched control mice, limb muscles of 6- to 17-month-old mdx mice are larger but weaker, with lower normalised force and power, whereas those from 24- to 28-month-old mdx mice are smaller and weaker. 2. The maximum isometric tetanic force (P(o)) and power output of limb muscles from 6-, 17-, 24- and 28-month-old mdx and control mice were measured in vitro at 25 degrees C and normalised with respect to cross-sectional area and muscle mass, respectively. 3. Body mass at 6 and 28 months was not significantly different in mdx and control mice, but that of control mice increased 16 % by 17 months and then declined 32 % by 28 months. The body masses of mdx mice declined linearly with age with a decrease of 25 % by 28 months. From 6 to 28 months of age, the range in the decline in the masses of EDL and soleus muscles of mdx and control mice was from 16 to 28 %. The muscle masses of mdx mice ranged from 9 % to 42 % greater than those of control mice at each of the four ages and, even at 28 months, the masses of EDL and soleus muscles of mdx mice were 17 % and 22 % greater than control values. 4. For mdx mice of all ages, muscle hypertrophy was highly effective in the maintenance of control values for absolute force for both EDL and soleus muscles and for absolute power of soleus muscles. Throughout their lifespan, muscles of mdx mice displayed significant weakness with values for specific P(o) and normalised power approximately 20 % lower than values for control mice at each age. For muscles of both strains, normalised force and power decreased approximately 28 % with age, and consequently weakness was more severe in muscles of old mdx than in those of old control mice.

Animals↗

PubMed2001

In vivo and in vitro correction of the mdx dystrophin gene nonsense mutation by short-fragment homologous replacement.

Targeted genetic correction of mutations in cells is a potential strategy for treating human conditions that involve nonsense, missense, and transcriptional splice junction mutations. One method of targeted gene repair, single-stranded short-fragment homologous replacement (ssSFHR), has been successful in repairing the common deltaF508 3-bp microdeletion at the cystic fibrosis transmembrane conductance regulator (CFTR) locus in 1% of airway epithelial cells in culture. This study investigates in vitro and in vivo application of a double-stranded method variant of SFHR gene repair to the mdx mouse model of Duchenne muscular dystrophy (DMD). A 603-bp wild-type PCR product was used to repair the exon 23 C-to-T mdx nonsense transition at the Xp21.1 dys locus in cultured myoblasts and in tibialis anterior (TA) from male mdx mice. Multiple transfection and variation of lipofection reagent both improved in vitro SFHR efficiency, with successful conversion of mdx to wild-type nucleotide at the dys locus achieved in 15 to 20% of cultured loci and in 0.0005 to 0.1% of TA. The genetic correction of mdx myoblasts was shown to persist for up to 28 days in culture and for at least 3 weeks in TA. While a high frequency of in vitro gene repair was observed, the lipofection used here appeared to have adverse effects on subsequent cell viability and corrected cells did not express dystrophin transcript. With further improvements to in vitro and in vivo gene repair efficiencies, SFHR may find some application in DMD and other genetic neuromuscular disorders in humans.

Animals↗

PubMed2001

Hyperbaric oxygen modulates antioxidant enzyme activity in rat skeletal muscles.

In skeletal muscle the activity of the enzymatic antioxidants superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) is regulated in response to generation of reactive oxygen species (ROS). Increased activity of these enzymes is observed after repeated bouts of aerobic exercise, a potent stimulus for intracellular ROS production. Hyperbaric oxygen (HBO) inhalation also stimulates intracellular ROS production although the effects of HBO on skeletal muscle SOD, GPx and CAT activity have not been studied. We tested the hypothesis that SOD, GPx and CAT activity is modulated in skeletal muscles in response to acute and repeated HBO administration. In adult male rats acute HBO inhalation (60 mm at 3 atmospheres absolute) reduced catalase activity by approximately 51% in slow-twitch soleus muscles. Additionally, repeated HBO inhalation (twice daily for 28 days) increased Mn2+-superoxide dismutase activity by approximately 241% in fast-twitch extensor digitorum longus muscles. We conclude that both acute and repeated HBO inhalation can alter enzymatic antioxidant activity in skeletal muscles.

Animals↗

PubMed2001

Force and power output of diaphragm muscle strips from mdx and control mice after clenbuterol treatment.

Based on its anabolic properties, treatment with the beta(2)-adrenoceptor agonist, clenbuterol, has been proposed as a strategy for ameliorating the symptoms of muscular dystrophy. In the dystrophic mdx mouse, only the diaphragm muscle exhibits progressive and severe degeneration in muscle structure and function similar to that observed in Duchenne muscular dystrophy. We tested the hypothesis that 20 weeks of clenbuterol treatment ( approximately 1.5-2 mg kg(-1)day(-1)) would increase the force and power output of diaphragm muscle strips of 6-month-old mdx and control mice. At this age, the diaphragm muscles of mdx mice show extensive degeneration and impaired contractility compared with control mice. Clenbuterol treatment did not increase the normalized force or power output of diaphragm strips from either mdx or control mice. The degeneration and necrosis within the diaphragm muscle of mdx mice was also not ameliorated by clenbuterol treatment. The results indicate that clenbuterol treatment does not improve the structure or function of diaphragm muscles from mdx mice.

Adrenergic beta-Agonists↗

PubMed2001

IGF-I treatment improves the functional properties of fast- and slow-twitch skeletal muscles from dystrophic mice.

Although insulin-like growth factor-I (IGF-I) has been proposed for use by patients suffering from muscle wasting conditions, few studies have investigated the functional properties of dystrophic skeletal muscle following IGF-I treatment. 129P1 ReJ-Lama2(dy) (129 ReJ dy/dy) dystrophic mice suffer from a deficiency in the structural protein, laminin, and exhibit severe muscle wasting and weakness. We tested the hypothesis that 4 weeks of IGF-I treatment ( approximately 2 mg/kg body mass, 50 g/h via mini-osmotic pump, subcutaneously) would increase the mass and force producing capacity of skeletal muscles from dystrophic mice. IGF-I treatment increased the mass of the extensor digitorum longus (EDL) and soleus muscles of dystrophic mice by 20 and 29%, respectively, compared with untreated dystrophic mice (administered saline-vehicle only). Absolute maximum force (P(o)) of the EDL and soleus muscle was increased by 40 and 32%, respectively, following IGF-I treatment. Specific P(o) (sP(o)) was increased by 23% in the EDL muscles of treated compared with untreated mice, but in the soleus muscle sP(o) was unchanged. IGF-I treatment increased the proportion of type IIB and type IIA fibres and decreased the proportion of type I fibres in the EDL muscles of dystrophic mice. In the soleus muscles of dystrophic mice, IGF-I treatment increased the proportion of type IIA fibres and decreased the proportion of type I fibres. Average fibre cross-sectional area was increased in the EDL and soleus muscles of treated compared with untreated mice. We conclude that IGF-I treatment ameliorates muscle wasting and improves the functional properties of skeletal muscles of dystrophic mice. The findings have important implications for the role of IGF-I in ameliorating muscle wasting associated with the muscular dystrophies.

Animals↗

PubMed2001

Rigor force responses of permeabilized fibres from fast and slow skeletal muscles of aged rats.

1. Ageing is generally associated with a decline in skeletal muscle mass and strength and a slowing of muscle contraction, factors that impact upon the quality of life for the elderly. The mechanisms underlying this age-related muscle weakness have not been fully resolved. The purpose of the present study was to determine whether the decrease in muscle force as a consequence of age could be attributed partly to a decrease in the number of cross-bridges participating during contraction. 2. Given that the rigor force is proportional to the approximate total number of interacting sites between the actin and myosin filaments, we tested the null hypothesis that the rigor force of permeabilized muscle fibres from young and old rats would not be different. 3. Permeabilized fibres from the extensor digitorum longus (fast-twitch; EDL) and soleus (predominantly slow-twitch) muscles of young (6 months of age) and old (27 months of age) male F344 rats were activated in Ca2+-buffered solutions to determine force-pCa characteristics (where pCa = -log(10)[Ca2+]) and then in solutions lacking ATP and Ca2+ to determine rigor force levels. 4. The rigor forces for EDL and soleus muscle fibres were not different between young and old rats, indicating that the approximate total number of cross-bridges that can be formed between filaments did not decline with age. We conclude that the age-related decrease in force output is more likely attributed to a decrease in the force per cross-bridge and/or decreases in the efficiency of excitation-contraction coupling.

Aging↗

PubMed2001

Therapies for improving muscle function in neuromuscular disorders.

Muscle atrophy or wasting is a loss of muscle tissue resulting from disease or lack of use. This review examines recent pharmacologic or nutrition interventions for ameliorating wasting and improving muscle function in neuromuscular disorders. The information has application for treating the muscular dystrophies, cancer cachexia, weightlessness, immobilization, denervation, and disuse atrophy.

Adjuvants, Immunologic↗

PubMed2001

Redox modulation of maximum force production of fast-and slow-twitch skeletal muscles of rats and mice.

We used intact fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus muscles from rats and mice to test the hypothesis that exogenous application of an oxidant would increase maximum isometric force production (P(o)) of slow-twitch muscles to a greater extent than fast-twitch skeletal muscles. Exposure to an oxidant, hydrogen peroxide (H(2)O(2); 100 microM to 5 mM, 30 min), affected P(o) of rat muscles in a time- and dose-dependent manner. P(o) of rat soleus muscles was increased by 8 +/- 1 (SE) and 14 +/- 1% (P < 0.01) after incubation with 1 and 5 mM H(2)O(2), respectively, whereas in mouse soleus muscles P(o) was only increased after incubation with 500 microM H(2)O(2). P(o) of rat EDL muscles was affected by H(2)O(2) biphasically; initially there was a small increase (3 +/- 1%), but then P(o) diminished significantly after 30 min of treatment. In contrast, all concentrations of H(2)O(2) tested decreased P(o) of mouse EDL muscles. A reductant, dithiothreitol (DTT; rat = 10 mM, mouse = 1 mM), was added to quench H(2)O(2), and it reversed the potentiation in P(o) in rat soleus but not in rat EDL muscles or in any H(2)O(2)-treated mouse muscles. After prolonged equilibration (30 min) with 5 mM H(2)O(2) without prior activation, P(o) was potentiated in rat soleus but not EDL muscles, demonstrating that the effect of oxidation in the soleus muscles was also dependent on the activation history of the muscle. The results of these experiments demonstrate that P(o) of both slow- and fast-twitch muscles from rats and mice is modified by redox modulation, indicating that maximum P(o) of mammalian skeletal muscles is dependent on oxidation.

Animals↗

PubMed2001

Specific force of the rat extraocular muscles, levator and superior rectus, measured in situ.

Extraocular muscles are characterized by their faster rates of contraction and their higher resistance to fatigue relative to limb skeletal muscles. Another often reported characteristic of extraocular muscles is that they generate lower specific forces (sP(o), force per muscle cross-sectional area, kN/m(2)) than limb skeletal muscles. To investigate this perplexing issue, the isometric contractile properties of the levator palpebrae superioris (levator) and superior rectus muscles of the rat were examined in situ with nerve and blood supply intact. The extraocular muscles were attached to a force transducer, and the cranial nerves exposed for direct stimulation. After determination of optimal muscle length (L(o)) and stimulation voltage, a full frequency-force relationship was established for each muscle. Maximum isometric tetanic force (P(o)) for the levator and superior rectus muscles was 177 +/- 13 and 280 +/- 10 mN (mean +/- SE), respectively. For the calculation of specific force, a number of rat levator and superior rectus muscles were stored in a 20% nitric acid-based solution to isolate individual muscle fibers. Muscle fiber lengths (L(f)) were expressed as a percentage of overall muscle length, allowing a mean L(f) to L(o) ratio to be used in the estimation of muscle cross-sectional area. Mean L(f):L(o) was determined to be 0.38 for the levator muscle and 0.45 for the superior rectus muscle. The sP(o) for the rat levator and superior rectus muscles measured in situ was 275 and 280 kN/m(2), respectively. These values are within the range of sP(o) values commonly reported for rat skeletal muscles. Furthermore P(o) and sP(o) for the rat levator and superior rectus muscles measured in situ were significantly higher (P < 0.001) than P(o) and sP(o) for these muscles measured in vitro. The results indicate that the force output of intact extraocular muscles differs greatly depending on the mode of testing. Although in vitro evaluation of extraocular muscle contractility will continue to reveal important information about this group of understudied muscles, the lower sP(o) values of these preparations should be recognized as being significantly less than their true potential. We conclude that extraocular muscles are not intrinsically weaker than skeletal muscles.

Animals↗

PubMed2000

Functional properties of regenerating skeletal muscle following LIF administration.

We tested the hypothesis that periodic systemic administration of the myogenic cytokine leukemia inhibitory factor (LIF) enhances the functional recovery of regenerating skeletal muscle following bupivacaine-induced degeneration. LIF had no effect on functional capacity or regenerating myofiber size in rat muscles at 7, 14, or 21 days post-injury. The results do not support exogenous administration of LIF as a treatment for acute muscle injury, but a more frequent dosing regimen should be tested.

Animals↗

PubMed2000

Leukemia inhibitory factor ameliorates muscle fiber degeneration in the mdx mouse.

Although the muscles of the mdx mouse lack dystrophin, the protein absent in muscles of humans affected with Duchenne muscular dystrophy (DMD), the only mdx muscle to degenerate in a manner similar to those of DMD boys is the diaphragm. We have previously shown that leukemia inhibitory factor (LIF) is a trauma factor that enhances muscle repair in vivo and, when applied exogenously, increases the fiber size of mdx skeletal muscle. Furthermore, we developed a controlled release device for LIF based on a calcium alginate rod (release rate about 0.5% per day). These rods were sutured to the abdominal surface of the hemidiaphragm of mdx mice 3 months old. At age 6 months the mice were killed and the diaphragm muscles fixed and sectioned. The sections showed obvious muscle degeneration at 3 months of age in mdx mouse diaphragms and further degeneration at 6 months in saline-perfused muscle. Hemidiaphragm muscles continuously exposed to LIF over the same period contained more normal myofibers, larger regenerated fibers, and less adipose tissue and other non-contractile tissue. Morphometric analysis of the diaphragm sections was carried out. The LIF-treated animals showed a significant increase in fiber number and size compared to saline rod controls. The amount of nonmuscle (connective tissue and adipose tissue) was significantly reduced and the maximum force-producing capacity of isolated diaphragm muscle strips was higher in LIF-treated mice. The results demonstrate that LIF treatment ameliorates the dystrophic abnormalities in mdx mouse diaphragm.

Animals↗

PubMed2000

Hydrogen peroxide modulates Ca2+-activation of single permeabilized fibres from fast- and slow-twitch skeletal muscles of rats.

We examined the effects of redox modulation on single membrane-permeabilized fibre segments from the fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus muscles of adult rats to determine whether the contractile apparatus was the redox target responsible for the increased contractility of muscles exposed to low concentrations of H2O2. The effects of H2O2 on maximum Ca2+-activated force were dose-dependent with 30 min exposure to 5 mM H2O2 causing a progressive decrease by 22+/-3 and 13+/-2% in soleus and EDL permeabilized muscle fibres, respectively. Lower concentrations of exogenous H2O2 (100 microM and 1 mM) had no effect on maximum Ca2+-activated force. Subsequent exposure to the reductant dithiothreitol (DTT, 10 mM, 10 min) fully reversed the H2O2-induced depression of force in EDL, but not in soleus muscle fibres. Incubation with DTT alone for 10 min did not alter Ca2+-activated force in either soleus or EDL muscle fibres. The sensitivity of the contractile filaments to Ca2+ (pCa50) was not altered by exposure to any concentration of exogenous H2O2. However, all concentrations of H2O2 diminished the Hill coefficient in permeabilized fibres from the EDL muscle, indicating that the cooperativity of Ca2+ binding to troponin is altered. H2O2 (5 mM) did not affect rigor force, which indicates that the number of crossbridges participating in contraction was not reduced. In conclusion, H2O2 may reduce the maximum Ca2+ activated force production in skinned muscle fibres by decreasing the force per crossbridge.

Animals↗

PubMed2000

Contraction-induced injury to single permeabilized muscle fibers from mdx, transgenic mdx, and control mice.

Muscle fibers of mdx mice that lack dystrophin are more susceptible to contraction-induced injury, particularly when stretched. In contrast, transgenic mdx (tg-mdx) mice, which overexpress dystrophin, show no morphological or functional signs of dystrophy. Permeabilization disrupts the sarcolemma of fibers from muscles of mdx, tg-mdx, and control mice. We tested the null hypothesis stating that, after single stretches of maximally activated single permeabilized fibers, force deficits do not differ among fibers from extensor digitorum longus muscles of mdx, tg-mdx, or control mice. Fibers were maximally activated by Ca(2+) (pCa 4.5) and then stretched through strains of 10%, 20%, or 30% of fiber length (L(f)) at a velocity of 0.5 L(f)/s. Immediately after each strain, the force deficits were not different for fibers from each of the three groups of mice. When collated with studies of membrane-intact fibers in whole muscles of mdx, tg-mdx, and control mice, these results indicate that dystrophic symptoms do not arise from factors within myofibrils but, rather, from disruption of the sarcolemmal integrity that normally provides protection from contraction-induced injury.

Animals↗

PubMed2000

Hyperbaric oxygen improves contractile function of regenerating rat skeletal muscle after myotoxic injury.

There is growing interest in hyperbaric oxygen (HBO) as an adjunctive treatment for muscle injuries. This experiment tested the hypothesis that periodic inhalation of HBO hastens the functional recovery and myofiber regeneration of skeletal muscle after myotoxic injury. Injection of the rat extensor digitorum longus (EDL) muscle with bupivacaine hydrochloride causes muscle degeneration. After injection, rats breathed air with or without periodic HBO [100% O(2) at either 2 or 3 atmospheres absolute (ATA)]. In vitro maximum isometric tetanic force of injured EDL muscles and regenerating myofiber size were unchanged between 2 ATA HBO-treated and untreated rats at 14 days postinjury but were approximately 11 and approximately 19% greater, respectively, in HBO-treated rats at 25 days postinjury. Maximum isometric tetanic force of injured muscles was approximately 27% greater, and regenerating myofibers were approximately 41% larger, in 3 ATA HBO-treated rats compared with untreated rats at 14 days postinjury. These findings demonstrate that periodic HBO inhalation increases maximum force-producing capacity and enhances myofiber growth in regenerating skeletal muscle after myotoxic injury with greater effect at 3 than at 2 ATA.

Animals↗

PubMed2000

Deleterious effects of chronic clenbuterol treatment on endurance and sprint exercise performance in rats.

The beta(2)-adrenergic agonist, clenbuterol, has powerful muscle anabolic and lipolytic effects and is used by athletes to improve exercise performance; however, its use in conjunction with different forms of exercise training has received limited attention. Since previous studies have reported that chronic use of other beta(2)-adrenergic agonists has deleterious effects on cardiac muscle structure and function, the aim of the present study was to determine whether chronic clenbuterol administration would reduce the exercise capabilities of rats subjected to long-term treadmill sprint running, endurance swimming or voluntary wheel running training. The effect of clenbuterol treatment on exercise performance in rats was evaluated in three separate studies. Different groups of male rats were assigned to an endurance swimming (2 h/day, 5/7 days, 18 weeks) group, a treadmill sprint running (8x1 min bouts, 1.05 m/s, 20 weeks) group, or a voluntary wheel running (16 weeks) group. In each study, rats were allocated into either a treated group that received clenbuterol (2 mg.kg(-1).day(-1)) in their drinking water or an untreated control group. In each of the three studies, treated rats exhibited a reduction in exercise performance compared with untreated rats. Treated rats ran approximately 57% less total distance than untreated rats in the voluntary running programme and were unable to complete the swimming and sprinting protocols performed by the untreated rats. In each of the studies, the treated rats exhibited cardiac hypertrophy, with absolute heart mass increased by approximately 19% and heart mass relative to body mass increased by approximately 20%. The hearts of sedentary rats treated with clenbuterol exhibited extensive collagen infiltration surrounding blood vessels and in the wall of the left ventricle. The results indicate strongly that chronic clenbuterol administration deleteriously affects exercise performance in rats, potentially due to alterations in cardiac muscle structure and function.

Adrenergic beta-Agonists↗