Biomedical subjects

Gordon S Lynch

Publications and source records attributed to Gordon S Lynch.

30 records · Page 2Linked to original sources

PubMed2004

Emerging drugs for sarcopenia: age-related muscle wasting.

Sarcopenia is the term widely used to describe the progressive loss of muscle mass with advancing age. Even before significant muscle wasting becomes apparent, ageing is associated with a slowing of movement and a gradual decline in muscle strength, factors that increase the risk of injury from sudden falls and the reliance of the frail elderly on assistance in accomplishing even basic tasks of independent living. Sarcopenia is recognised as one of the major public health problems now facing industrialised nations, and its effects are expected to place increasing demands on public healthcare systems worldwide. Although the effects of ageing on skeletal muscle are unlikely to be halted or reversed, the underlying mechanisms responsible for these deleterious changes present numerous targets for drug discovery with potential opportunities to attenuate muscle wasting, improve muscle function, and preserve functional independence. Very few drugs have been developed with sarcopenia specifically in mind. However, because many of the effects of ageing on skeletal muscle resemble those indicated in many neuromuscular disorders, drugs that target neurodegenerative diseases may also have important relevance for treating age-related muscle wasting and weakness. This review describes a selection of the emerging drugs that have been developed during the period 1997 - 2004, relevant to sarcopenia.

Aged↗

PubMed2003

Beta 2-agonist administration reverses muscle wasting and improves muscle function in aged rats.

The beta2-adrenoceptor agonist (beta2-agonist) fenoterol has potent anabolic effects on rat skeletal muscle. We conducted an extensive dose-response study to determine the most efficacious dose of fenoterol for increasing skeletal muscle mass in adult rats and used this dose in testing the hypothesis that fenoterol may have therapeutic potential for ameliorating age-related muscle wasting and weakness. We used adult (16-month-old) rats that had completed their growth and development, and old (28-month-old) rats that exhibited characteristic muscle wasting and weakness, and treated them daily with either fenoterol (1.4 mg kg(-1), i.p), or saline vehicle, for 4 weeks. Following treatment, functional characteristics of fast-twitch extensor digitorum longus (EDL) and predominantly slow-twitch soleus muscles of the hindlimb were assessed in vitro. Untreated old rats exhibited a loss of skeletal muscle mass and a decrease in force-producing capacity, in both fast and slow muscles, compared with adult rats (P < 0.05). However, there was no age-associated decrease in skeletal muscle beta-adrenoceptor density, nor was the muscle response to chronic beta-agonist stimulation reduced with age. Thus, muscle mass and force-producing capacity of EDL and soleus muscles from old rats treated with fenoterol was equivalent to, or greater than, untreated adult rats. The increase in mass and strength was attributed to a non-selective increase in the cross-sectional area of all muscle fibre types, in both the EDL and soleus. Fenoterol treatment caused a small increase in fatiguability due to a decrease in oxidative metabolism in both EDL and soleus muscles, with some cardiac hypertrophy. Further studies are needed to fully separate the desirable effects on skeletal muscle and the undesirable effects on the heart. Nevertheless, our results demonstrate that fenoterol is a powerful anabolic agent that can restore muscle mass and strength in old rats, and provide preliminary evidence of therapeutic potential for age-related muscle wasting and weakness.

Adrenergic beta-2 Receptor Agonists↗

PubMed2003

Beta2-adrenoceptor agonist fenoterol enhances functional repair of regenerating rat skeletal muscle after injury.

Beta(2)-adrenoceptor agonists such as fenoterol are anabolic in skeletal muscle, and because they promote hypertrophy and improve force-producing capacity, they have potential application for enhancing muscle repair after injury. No previous studies have measured the beta(2)-adrenoceptor population in regenerating skeletal muscle or determined whether fenoterol can improve functional recovery in regenerating muscle after myotoxic injury. In the present study, the extensor digitorum longus (EDL) muscle of the right hindlimb of deeply anesthetized rats was injected with bupivacaine hydrochloride, which caused complete degeneration of all muscle fibers. The EDL muscle of the left hindlimb served as the uninjured control. Rats received either fenoterol (1.4 mg x kg(-1) x day(-1)) or an equal volume of saline for 2, 7, 14, or 21 days. Radioligand binding assays identified a approximately 3.5-fold increase in beta(2)-adrenoceptor density in regenerating muscle at 2 days postinjury. Isometric contractile properties of rat EDL muscles were measured in vitro. At 14 and 21 days postinjury, maximum force production (P(o)) of injured muscles from fenoterol-treated rats was 19 and 18% greater than from saline-treated rats, respectively, indicating more rapid restoration of function after injury. The increase in P(o) in fenoterol-treated rats was due to increases in muscle mass, fiber cross-sectional area, and protein content. These findings suggest a physiological role for beta(2)-adrenoceptor-mediated mechanisms in muscle regeneration and show clearly that fenoterol hastens recovery after injury, indicating its potential therapeutic application.

Adrenergic beta-Agonists↗

PubMed2003

Depolarization-induced contraction and SR function in mechanically skinned muscle fibers from dystrophic mdx mice.

Dystrophin is absent in muscle fibers of patients with Duchenne muscular dystrophy (DMD) and in muscle fibers from the mdx mouse, an animal model of DMD. Disrupted excitation-contraction (E-C) coupling has been postulated to be a functional consequence of the lack of dystrophin, although the evidence for this is not entirely clear. We used mechanically skinned fibers (with a sealed transverse tubular system) prepared from fast extensor digitorum longus muscles of wild-type control and dystrophic mdx mice to test the hypothesis that dystrophin deficiency would affect the depolarization-induced contractile response (DICR) and sarcoplasmic reticulum (SR) function. DICR was similar in muscle fibers from mdx and control mice, indicating normal voltage regulation of Ca2+ release. Nevertheless, rundown of DICR (<50% of initial) was reached more rapidly in fibers from mdx than control mice [control: 32 +/- 5 depolarizations (n = 14 fibers) vs. mdx: 18 +/- 1 depolarizations (n = 7) before rundown, P < 0.05]. The repriming rate for DICRs was decreased in fibers from mdx mice, with lower submaximal DICR observed after 5, 10, and 20 s of repriming compared with fibers from control mice (P < 0.05). SR Ca2+ reloading was not different in fibers from control and mdx mice, and no difference was observed in SR Ca2+ leak. Caffeine (2-7 mM)-induced contraction was diminished in fibers from mdx mice compared with control (P < 0.05), indicating depressed SR Ca2+ release channel activity. Our findings indicate that fast fibers from mdx mice exhibit some impairment in the events mediating E-C coupling and SR Ca2+ release channel activity.

Animals↗

PubMed2003

Therapeutic clenbuterol treatment does not alter Ca2+ sensitivity of permeabilized fast muscle fibres from exercise trained or untrained horses.

Clenbuterol is a beta2-adrenoceptor agonist primarily used for treating bronchospasm and alleviating the symptoms of chronic obstructive pulmonary disease (COPD) in the horse. In other species (rats, mice, sheep, and cattle), chronic high doses of clenbuterol (typically in the milligram per kilogram body weight range) has been shown to cause a muscle directed protein anabolic response. Clenbuterol can also modify muscle fibre composition and therefore potentially affect muscle function. This has implications for the performance of exercising horses being treated with therapeutic doses of clenbuterol (typically in the microgram per kilogram body weight range) for bronchospasm or COPD. It is not known whether clenbuterol treatment affects muscle fibre function in horses. The purpose of this study was to examine the effects of a therapeutic dose of clenbuterol, with and without exercise, on the contractile activation characteristics of single membrane permeabilized fibres prepared from muscle biopsies. We tested the hypothesis that therapeutic treatment with clenbuterol would not affect muscle fibre function. Unfit Standardbred mares were treated for 8 weeks with; clenbuterol (2.4 microg/kg twice/day, 5 days/week) plus exercise (20 min at 50% VO2(max) 3 d/wk; CLENEX), clenbuterol only (CLEN), or exercise only (EX). Muscle biopsies were taken from the gluteus medius muscle before and after treatment and stored in a glycerol-based solution to prepare permeabilized muscle fibres. The force-pCa relationship for fibres from CLEN horses was steeper (P < 0.05) indicative of greater cooperative interactions within the thin filament, however, fibre sensitivity to Ca2+ was unchanged. In contrast, the steepness of the force-pCa relationship was not changed in fibres from EX and CLENEX horses and Ca2+ sensitivity was also unaffected. Rigor force, activation in the absence of ATP, was not affected by any treatment indicating an approximately equivalent number of participating cross-bridges during activation. The results indicate that a therapeutic dose of clenbuterol to Standardbred horses does not affect the Ca(2+)-activated contractile characteristics of isolated muscle fibres.

Adrenergic beta-Agonists↗

PubMed2002

Beta 2-agonist fenoterol has greater effects on contractile function of rat skeletal muscles than clenbuterol.

Potential treatments for skeletal muscle wasting and weakness ideally possess both anabolic and ergogenic properties. Although the beta(2)-adrenoceptor agonist clenbuterol has well-characterized effects on skeletal muscle, less is known about the therapeutic potential of the related beta(2)-adrenoceptor agonist fenoterol. We administered an equimolar dose of either clenbuterol or fenoterol to rats for 4 wk to compare their effects on skeletal muscle and tested the hypothesis that fenoterol would produce more powerful anabolic and ergogenic effects. Clenbuterol treatment increased fiber cross-sectional area (CSA) by 6% and maximal isometric force (P(o)) by 20% in extensor digitorum longus (EDL) muscles, whereas fiber CSA in soleus muscles decreased by 3% and P(o) was unchanged, compared with untreated controls. In the EDL muscles, fenoterol treatment increased fiber CSA by 20% and increased P(o) by 12% above values achieved after clenbuterol treatment. Soleus muscles of fenoterol-treated rats exhibited a 13% increase in fiber CSA and a 17% increase in P(o) above that of clenbuterol-treated rats. These data indicate that fenoterol has greater effects on the functional properties of rat skeletal muscles than clenbuterol.

Adrenal Glands↗

PubMed2002

Excitation-contraction coupling and sarcoplasmic reticulum function in mechanically skinned fibres from fast skeletal muscles of aged mice.

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. Alterations in Ca2+ handling are thought to contribute to these age-related changes in muscle contractility, yet the effects of ageing on sarcoplasmic reticulum (SR) Ca2+ handling and the Ca2+ transport system remain unresolved. We used mechanically skinned single fibres from the fast twitch extensor digitorum longus (EDL) muscles from young (4-month-old) and old (27- to 28-month-old) mice to test the hypothesis that the age-related changes in skeletal muscle contractility, especially the slower rate of contraction, are due to changes intrinsic to the muscle fibres. There were no age-related differences in the peak height of depolarization-induced contractile response (DICR) or the number of DICRs elicited before rundown (DICR < 50 % of initial). The time taken to reach peak DICR (TPDICR) was approximately12 % slower in single muscle fibres from old compared with young mice (P < 0.05). The rate of relaxation following DICR was not different in young and old mice. Examination of SR function demonstrated that SR Ca2+ reloading in Ca2+ -depleted skinned fibres was not different in young and old mice, nor was there any age-related difference in Ca2+ leak from the SR. However, low [caffeine] contracture in fibres from old mice was only half of that observed in fibres from young mice (P < 0.05), indicating a lower sensitivity of the SR Ca2+ release channel (CRC) to caffeine. We found no difference in maximum Ca2+ -activated force (P(o)) or specific force (sP(o); P(o) corrected for cross-sectional area) in EDL muscle fibres from young and old mice. Impaired excitation-contraction (E-C) coupling and a decrease in SR CRC function are mechanisms which are likely to contribute to the overall slowing of muscle contraction with age.

Aging↗

PubMed2002

Hydrogen peroxide increases depolarization-induced contraction of mechanically skinned slow twitch fibres from rat skeletal muscles.

The effect of exogenous hydrogen peroxide (H(2)O(2)) on excitation-contraction (E-C) coupling and sarcoplasmic reticulum (SR) function was compared in mechanically skinned slow twitch fibres (prepared from the soleus muscles) and fast twitch fibres (prepared from the extensor digitorum longus; EDL muscles) of adult rats. Equilibration (5 min) with 1 mM H(2)O(2) diminished the ability of the Ca(2+)-depleted SR to reload Ca(2+) in both slow (P < 0.01) and fast twitch fibres (P < 0.05) compared to control. Under conditions when all Ca(2+) uptake was prevented, 1 mM H(2)O(2) increased SR Ca(2+) "leak" in fast twitch fibres by 24 +/- 5 % (P < 0.05), but leak was not altered in slow twitch fibres. Treatment with 1 mM H(2)O(2) also increased the peak force of low [caffeine] contracture by approximately 45% in both fibre types compared to control (P < 0.01), which could be partly reversed following treatment with 10 mM dithiothreitol (DTT). The changes in SR function caused by 1 mM H(2)O(2) were associated with an approximately 65% increase in the peak height of depolarization-induced contractile response (DICR) in slow twitch fibres, compared to control (no H(2)O(2); P < 0.05). In contrast, peak contractile force of fast twitch fibres was not altered by 1 mM H(2)O(2) treatment. Equilibration with 5 mM H(2)O(2) induced a spontaneous force response in both slow and fast twitch fibres, which could be partly reversed by 2 min treatment with 10 mM DTT. Peak DICR was also increased approximately 40% by 5 mM H(2)O(2) in slow twitch fibres compared to control (no H(2)O(2); P < 0.05). Our results indicate that exogenous H(2)O(2) increases depolarization-induced contraction of mechanically skinned slow but not fast twitch fibres. The increase in depolarization-induced contraction in slow twitch fibres might be mediated by an increased SR Ca(2+) release during contraction and/or an increase in Ca(2+) sensitivity.

Animals↗

PubMed2002

Effects of leukemia inhibitory factor on rat skeletal muscles are modulated by clenbuterol.

Leukemia inhibitory factor (LIF) is implicated in skeletal muscle regeneration, but the effect of exogenous LIF on uninjured muscles is not known. We tested the hypothesis that LIF administration would stimulate muscle hypertrophy, with an increased effect during clenbuterol-induced fiber remodeling. Rats received daily injections of either saline or LIF, and either regular or clenbuterol-supplemented drinking water for 4 weeks. In the slow-twitch soleus muscles of LIF-treated rats, specific force (sP(o)) and muscle fiber size were increased by approximately 13% and approximately 26%, respectively, compared to saline-treated rats. In the soleus muscles of rats receiving LIF and clenbuterol, compared to rats receiving clenbuterol alone, maximum isometric tension (P(o)) was approximately 19% greater. LIF alone did not affect the properties of fast-twitch extensor digitorum longus (EDL) muscles, but in rats receiving LIF and clenbuterol, compared to clenbuterol alone, EDL fiber size and muscle mass were increased by approximately 20% and approximately 10%, respectively. The hypertrophic effects of exogenous LIF on uninjured skeletal muscles indicate that LIF may have application in the treatment of conditions characterized by muscle wasting.

Adrenergic beta-Agonists↗

PubMed2002

Improved contractile function of the mdx dystrophic mouse diaphragm muscle after insulin-like growth factor-I administration.

Limited knowledge exists regarding the efficacy of insulin-like growth factor I (IGF-I) administration as a therapeutic intervention for muscular dystrophies, although findings from other muscle pathology models suggest clinical potential. The diaphragm muscles of mdx mice (a model for Duchenne muscular dystrophy) were examined after 8 weeks of IGF-I administration (1 mg/kg s.c.) to test the hypothesis that IGF-I would improve the functional properties of dystrophic skeletal muscles. Force per cross-sectional area was approximately 49% greater in the muscles of treated mdx mice (149.6 +/- 9.6 kN/m(2)) compared with untreated mice (100.1 +/- 4.6 kN/m(2), P < 0.05), and maintenance of force over repeated maximal contraction was enhanced approximately 30% in muscles of treated mice (P < 0.05). Diaphragm muscles from treated mice comprised fibers with approximately 36% elevated activity of the oxidative enzyme succinate dehydrogenase, and approximately 23% reduction in the proportion of fast IId/x muscle fibers with concomitant increase in the proportion of type IIa fibers compared with untreated mice (P < 0.05). The data demonstrate that IGF-I administration can enhance the fatigue resistance of respiratory muscles in an animal model of dystrophin deficiency, in conjunction with enhancing energenic enzyme activity. As respiratory function is a mortality predictor in Duchenne muscular dystrophy patients, further evaluation of IGF-I intervention is recommended.

Animals↗

PubMed2002

Hyperbaric oxygen increases the contractile function of regenerating rat slow muscles.

UNLABELLED: Human trials of hyperbaric oxygen (HBO) treatment of sports-related muscle injuries are equivocal. Although most human skeletal muscles are composed of mixed muscle fiber types, it is unclear whether HBO affects fiber types differently. PURPOSE: We tested the hypothesis that HBO can enhance the functional properties of regenerating rat soleus muscles that are composed predominantly of slow fibers. METHODS: After intramuscular injection of bupivacaine hydrochloride to induce the degeneration of all fibers within the soleus muscle, treated rats received daily HBO treatment at 3 atmospheres absolute. RESULTS: In untreated rats, injured muscles demonstrated a reduced force-producing capacity (control soleus vs injured soleus, 220.3 +/- 2.5 vs 157.6 +/- 3.3 kN.m(-2) at 25 d postinjury, respectively, P < 0.05) and contained smaller regenerating muscle fibers than uninjured soleus muscles (fiber cross sectional area in control soleus vs injured soleus, 2289 +/- 164 vs 1154 +/- 92 microm 2 at 25 d postinjury, respectively, P < 0.05). The regenerating soleus muscles of HBO-treated rats demonstrated a greater force-producing capacity as a percentage of contralateral control muscles than the regenerating muscles from untreated rats at 14 d postinjury (regenerating HBO-soleus peak tension and untreated soleus peak tension, 42.9 +/- 1.9 and 35.8 +/- 3.9% of contralateral control muscles, respectively, P < 0.05), but no effect of treatment was observed at 25 d postinjury. CONCLUSION: HBO enhanced the contractile properties of regenerating rat soleus muscles after myotoxic injury, but this improvement was not sustained for the duration of the regenerative process. The data indicate that the outcome of HBO treatment of a muscle injury may be influenced by the fiber type composition of the injured muscle.

Animals↗

PubMedDate not supplied

Endurance training adaptations modulate the redox-force relationship of rat isolated slow-twitch skeletal muscles.

1. Studies have shown that, in isolated skeletal muscles, maximum isometric force production (Po) is dependent on muscle redox state. Endurance training increases the anti-oxidant capacity of skeletal muscles, a factor that could impact on the force-producing capacity following exogenous exposure to an oxidant. We tested the hypothesis that 12 weeks treadmill training would increase anti-oxidant capacity in rat skeletal muscles and alter their response to exogenous oxidant exposure. 2. At the conclusion of the 12 week endurance-training programme, soleus (slow-twitch) muscles from trained rats had greater citrate synthase (CS) and catalase (CAT) activity compared with soleus muscles from untrained rats (P < 0.05). In contrast, CAT activity of extensor digitorum longus (EDL; fast-twitch) muscles from trained rats was not different to EDL muscles of untrained rats. The CS activity was lower in EDL muscles from trained compared with untrained rats (P < 0.05). 3. Equilibration with exogenous hydrogen peroxide (H2O2, 5 mmol/L) increased the Po of soleus muscles from untrained rats for the duration of treatment (30 min), whereas the Po of EDL muscles was affected biphasically, with a small increase initially (after 5 min), followed by a more marked decrease in Po (after 30 min). The H2O2-induced increase in Po of soleus muscles from trained rats was less than that in untrained rats (P < 0.05), but no differences were observed in the Po of EDL muscles following training. 4. The results indicate that 12 weeks endurance running training conferred adaptations in soleus but not EDL muscles. These adaptations were associated with an attenuation of the oxidant-induced increase in Po of soleus muscles from trained compared with untrained rats. We conclude that endurance training-adapted soleus muscles have a slightly altered redox-force relationship.

Adaptation, Physiological↗