Biomedical subjects

J A Faulkner

Publications and source records attributed to J A Faulkner.

At least 55 records · Page 3Linked to original sources

PubMed1995

Injury to muscle fibres after single stretches of passive and maximally stimulated muscles in mice.

1. Our purpose was to investigate the initial mechanisms responsible for contraction-induced injury. Most studies of mechanisms of contraction-induced injury have been based on observations made either shortly after many repeated contractions at the peak of fatigue, or days after, at the peak of delayed onset injury. As a result, conclusions based on these studies are complicated by interactions of mechanical and biochemical events, as well as the passage of time. We studied the initial mechanical events associated with contraction-induced injury immediately following single stretches of whole skeletal muscles of mice in situ. 2. We tested the hypothesis that immediately following a single stretch, the severity of contraction-induced injury is a function of both strain and average force. Consequently, the work done to stretch the muscle would be the best predictor of the magnitude of injury. Extensor digitorum longus muscles were adjusted to optimum length for force (L(o)). Passive (not stimulated) and maximally activated muscles were exposed to single stretches of 10, 20, 30, 50 or 60% strain, relative to muscle fibre length (Lf), at a rate of 2 Lf s-1. 3. The magnitude of injury was represented by the force deficit 1 min after the stretch expressed as a percentage of the maximum force prior to the stretch. The occurrence of injury was confirmed directly by electron microscopic analysis of the ultrastructure of muscle fibres that were fixed immediately following single stretches. 4. For active muscles, a single stretch of only 30% strain produced a significant force deficit, whereas for passive muscles, a larger strain was required. Stretches of greater than 50% strain resulted in greater force deficits for passive than for maximally activated muscles. For either condition, the work done to stretch the muscle was the best predictor of the magnitude of injury, accounting for 76% of the variability in the force deficit for maximally activated muscles, and 85% for passive muscles.

Animals↗

PubMed1995

Muscle atrophy and weakness with aging: contraction-induced injury as an underlying mechanism.

In old compared with young animals, muscle mass is decreased by 30% to 40%, and maximum force and power are decreased to an even greater extent. The age-related declines in muscle mass and muscle function are similar to those that occur with decreased physical activity. Despite the similarities, we conclude that the losses in muscle mass, force, and power are not due solely to old animals being less active, but rather accrue from intrinsic age-related changes in muscles and in muscle fibers that appear to be immutable and irreversible. The intrinsic changes are associated with denervation of fast fatigable fibers and motor units and motor unit remodeling, which may be initiated by contraction-induced injury. The mechanisms remain unresolved for the weakness, the fatigability, the high susceptibility to contraction-induced injury, and the impaired recovery from injury demonstrated by the skeletal muscles of old animals.

Adaptation, Physiological↗

PubMed1995

Expression of full-length and truncated dystrophin mini-genes in transgenic mdx mice.

Duchenne and Becker muscular dystrophy are caused by defects in the dystrophin gene, and are candidates for treatment by gene therapy. We have shown previously that overexpression of a full-length dystrophin cDNA prevents the development of dystrophic symptoms in mdx mice. We show here that this functional correction can be achieved by expressing the full-length muscle isoform at a lower level than is present in control animals. Gene therapy for DMD may necessitate the use of truncated dystrophin mini-genes to accommodate the limited cloning capacity of current-generation viral delivery vectors. We have constructed both murine and human mini-genes deleted for exons 17-48, and have demonstrated that expression of either mini-gene can almost completely prevent the development of dystrophic symptoms in transgenic mdx mice. These results suggest that viral-mediated expression of moderate levels of a truncated dystrophin could be an effective treatment for DMD.

Animals↗

PubMed1995

Muscle fatigue in old animals. Unique aspects of fatigue in elderly humans.

Muscle atrophy, weakness, injury, and fatigue are inevitable and immutable concomitants of old age. Atrophy results from a gradual process of fiber denervation with loss of some fibers and atrophy of others. Fast fibers show more denervation and atrophy than slow fibers. Some fast fibers are reinnervated by axonal sprouting from slow fibers resulting in remodeling of motor units. With aging, the decreases in strength and power are greater than expected from the loss in muscle mass. Contraction-induced injury is proposed as a mechanism of the fast fiber denervation. With atrophy and weakness, human beings show a dramatic decrease in endurance and increase in fatigability with aging, but strength and endurance training slows the process.

Aging↗

PubMed1994

Tubular nerve guide and epineurial repair: comparison of techniques for neurorrhaphy.

Experiments were conducted on 36 male, Sprague-Dawley rats. In 10 animals, neurorrhaphy was performed on the peroneal nerve with epineurial repair and, in 11 animals, with a tubular polyethylene nerve guide. The authors tested the hypothesis that, following transient denervation of a skeletal muscle by transection of a peroneal nerve, the restoration of maximum force and of maximum specific force developed after insertion of a tubular nerve guide, will not be different from that developed after microsurgical epineurial neurorrhaphy. The contractile properties of the extensor digitorum longus (EDL) muscle, innervated by the peroneal nerve, were evaluated after an average of 116 days. The maximum tetanic force of EDL muscles with epineurial repair and nerve guide were 84 percent and 75 percent, respectively, of the value for control EDL muscles. The specific forces of the muscles in both groups were not different from the control values. The conclusion is that, following stabilization after transection and repair, each of the two methods was equally effective in restoring the ability of the muscle to develop force.

Anastomosis, Surgical↗

PubMed1994

Prevention of dystrophic pathology in mdx mice by a truncated dystrophin isoform.

The C-terminal domain of dystrophin is alternatively spliced to produce a variety of tissue and developmental stage-specific isoforms. Recent studies suggest that the C-terminal domain binds to the dystrophin-associated glycoprotein complex (DGC) in muscle, but little is known about the functional significance of the alternative splicing or what role individual isoforms may play in specific tissues. The major dystrophin transcript in brain lacks exons 71-74, and encodes an isoform not observed in skeletal muscle. To explore the capacity of this truncated isoform to function in muscle, we have generated transgenic mice expressing a murine dystrophin mini-gene missing exons 71-74. Uniform expression of this construct on a mutant mdx mouse background results in normal muscle morphology and physiology, and prevents the development of muscular dystrophy. These mice also display normal expression and localization of the DGC, suggesting that the alternatively spliced exons are not required for dystrophin function in skeletal muscle. An additional line of mice was analyzed that had a mosaic pattern of expression. These mice display a markedly milder phenotype than mdx mice, despite the expression of dystrophin in only half the muscle fibers. These results indicate that viral delivery of dystrophin to a simple majority of fibers in a muscle group would greatly reduce the dystrophic pathology associated with Duchenne muscular dystrophy.

Alternative Splicing↗

PubMed1994

Isometric, shortening, and lengthening contractions of muscle fiber segments from adult and old mice.

In old animals, skeletal muscle force decreases during both isometric and shortening contractions. In contrast, force during lengthening appears to be unaffected by aging. We hypothesized that with aging single permeabilized muscle fibers would demonstrate the same impairments in force as are observed for whole muscles. For single permeabilized fibers from extensor digitorum longus muscles of adult and old mice, forces were measured during isometric, shortening, and lengthening contractions performed at 15 degrees C. Maximum isometric forces normalized for fiber area were not different for fibers from adult and old mice. During submaximal isometric contractions a decreased calcium sensitivity resulted in lower forces for fibers from old compared with adult mice. In contrast to a lack of difference in forces developed by fibers from old and adult mice during shortening contractions, during lengthening contractions fibers from old mice developed forces approximately 30% higher than those of adult mice. We conclude that the impairments in force of whole muscles with aging are not the result of impairments in intrinsic force-generating capacity of cross bridges, but changes do occur in single permeabilized muscle fibers of old mice that result in higher forces during stretch.

Aging↗

PubMed1994

Recovery of medial gastrocnemius muscle grafts in rats: implications for the plantar flexor group.

Medial gastrocnemius (MGN) muscles were grafted in 18 rats and evaluated at 60, 90, and 120 days after the operation. Our purpose was to investigate the degree of recovery of the vascularized MGN grafts and the entire plantar flexor muscle group. Compared with control values, muscle mass and maximum force of MGN grafts were decreased by 33 and 38% at 60 days, 22 and 32% at 90 days, and 13 and 15% at 120 days. At 60 and 90 days, the deficits in maximum force for the entire plantar flexor muscle group, including the graft, were 29 and 17%, respectively. No difference was observed at 120 days. At 60 days, the deficit in the total mass of the plantar flexor group was 14% compared with control values, but by 90 days no deficit was observed. The restoration of normal plantar flexor group structure and function indicates that the degree of recovery attained by MGN grafts, although not complete, was sufficient to ensure that the performance of the total muscle group was not compromised.

Adaptation, Physiological↗

PubMed1994

Skeletal muscle weakness in old age: underlying mechanisms.

Maintenance of muscle mass and strength contributes to mobility which impacts on quality of life. Although muscle atrophy, declining strength, and physical frailty are generally accepted as inevitable concomitants of aging, the causes are unknown. Clarification of the mechanisms responsible for these changes would enhance our understanding of the degree to which they are preventable or treatable. The decline in muscle function between maturity and old age is similar for muscles of many different animals including human beings, and is typified by the decreases of approximately 35% in maximum force, approximately 30% in maximum power, and 20% in normalized force (kN.m-2) and power (W.kg-1) of extensor digitorum longus (EDL) muscles in old compared with adult mice. Much of the age-associated muscle atrophy and declining strength may be explained by motor unit remodeling which appears to occur by selective denervation of muscle fibers with reinnervation by axonal sprouting from an adjacent innervated unit. Muscles in old mice appear more susceptible to injury than muscles in young or adult mice and have a decreased capacity for recovery. The process of age-related denervation may be aggravated by an increased susceptibility of muscles in old animals to contraction-induced injury coupled with impaired capacity for regeneration.

Adult↗

PubMed1993

Overexpression of dystrophin in transgenic mdx mice eliminates dystrophic symptoms without toxicity.

Duchenne and Becker muscular dystrophy (DMD and BMD) are X-linked recessive diseases caused by defective expression of dystrophin. The mdx mouse, an animal model for DMD, has a mutation that eliminates expression of the 427K muscle and brain isoforms of dystrophin. Although these animals do not display overt muscle weakness or impaired movement, the diaphragm muscle of the mdx mouse is severely affected and shows progressive myofibre degeneration and fibrosis which closely resembles the human disease. Here we explore the feasibility of gene therapy for DMD by examining the potential of a full-length dystrophin transgene to correct dystrophic symptoms in mdx mice. We find that expression of dystrophin in muscles of transgenic mdx mice eliminates the morphological and immunohistological symptoms of muscular dystrophy. In addition, overexpression of dystrophin prevents the development of the abnormal mechanical properties associated with dystrophic muscle without causing deleterious side effects. Our results provide functional evidence for the feasibility of gene therapy for DMD.

Animals↗

PubMed1993

Injury to skeletal muscle fibers during contractions: conditions of occurrence and prevention.

Contraction-induced injury results in the degeneration and regeneration of muscle fibers. Of the three types of contractions--shortening (concentric), isometric, and lengthening (eccentric)--injury is most likely to occur and the severity of the injury is greatest during lengthening contractions. The magnitude of the injury to muscle fibers may be assessed by direct measures of cellular and ultrastructural damage; by indirect measures of changes in enzyme efflux, calcium influx, ratio of oxidized to reduced glutathione, and force development; and, in human beings, by reports of muscle soreness. The sequence of events includes an initial injury that is primarily mechanical and a secondary metabolic, or biochemical, injury that peaks 1 to 3 days after the injurious contractions. The recovery from contraction-induced injury is usually complete within 30 days. Repeated exposures to protocols of lengthening contractions result in "trained" muscles that are not injured by the protocol that previously caused injury.

Animals↗

PubMed1993

Tenotomy and repair of latissimus dorsi muscles in rats: implications for transposed muscle grafts.

The functional properties of latissimus dorsi (LTD) muscles were evaluated 160 to 180 days after tenotomy and repair, when grafts had stabilized. Our hypothesis was that, compared with control LTD muscles, LTD grafts would develop less absolute force and power but that the specific force and normalized power would not differ. Expressed as a percentage of the value for control LTD muscles, values for grafts were 67% for muscle mass, 74% for mean single fiber cross-sectional area, 56% for maximum absolute isometric tetanic force, 64% for maximum absolute average force during shortening, and 70% for maximum absolute power. Compared with control LTD muscles, grafts showed no significant differences either in the number of fibers in the total muscle cross section or in the optimum velocity for the development of power. When force and power of grafts were normalized for total fiber cross-sectional area and mass, respectively, only the value for maximum specific force (84% of control value) was significant. The mechanisms responsible for the decrease in specific force after tenotomy and repair are not known. In contrast to the deficit in maximum specific force, the 30% deficit in maximum absolute power of grafts compared with control LTD muscles was explained completely by the 33% smaller muscle mass.

Animals↗

PubMed1992

Morphologic characteristics of muscles grafted in rabbits with neurovascular repair.

In 34 female white rabbits, rectus femoris (RFM) muscles were grafted with immediate anastomoses of the vasculature (VA) and with nerves either left intact (NI-VA) or with nerves repaired (NR-VA). The purpose of the study was to compare the morphologic changes that occur in NI-VA grafts and NR-VA grafts from 8 to 120 days after grafting. After 8 days, nearly complete survival of all muscle fibers was found. The muscle mass and single fiber cross-sectional area (CSA) of the NI-VA group remained near control values for the first 30 days and then declined to 82 percent and 62 percent of the control values, respectively. Little evidence of morphologic disruption was observed. The NR-VA grafts displayed a significant denervation atrophy within the first 15 days, with relative values 67 percent of the control value for mean mass and 53 percent for single fiber CSA. By 120 days, mass and CSA recovered to 80 percent and 62 percent of control values. Although the similarity of the deficits in the nerve-intact and nerve-repaired grafts suggest that tenotomy and repair, rather than innervation, were the major limitations, the mechanism was not resolved.

Adipose Tissue↗

PubMed1992

Injury to skeletal muscle during altitude training: induction and prevention.

A contracting skeletal muscle will shorten, remain isometric, or lengthen depending on the interaction between external load and the force developed by the muscle. Most physical activities involve shortening, isometric and lengthening contractions. The fluctuations in terrain encountered at altitude, increase both the likelihood that lengthening contractions will occur and the severity of the stretches. When performing a given amount of work, muscles lengthened during contractions expend less energy and fatigue less rapidly than muscles that shorten. Conversely, with equal activation, displacement, and velocity, the work done on a muscle during lengthening contractions is greater than the work performed by a muscle during shortening contractions, but force decreases more rapidly during lengthening. Furthermore, muscles are more likely to be injured during lengthening contractions than during shortening or isometric contractions. The occurrence of contraction-induced injury can be eliminated, or minimized, by prior training specific for the performance of lengthening contractions.

Altitude↗

PubMed1992

Parallel-fibered muscles transplanted with neurovascular repair into bipennate muscle sites in rabbits.

Experiments were performed on 20 New Zealand White male rabbits. Our hypotheses were that (1) latissimus dorsi (LTD) muscles transplanted into the site of a bipennate rectus femoris (RFM) muscle with neurovascular repair would retain their parallel-fibered structure and (2) the parallel-fibered structure of latissimus dorsi grafts would reduce their total fiber cross-sectional area and adversely affect force development relative to that of bipennate rectus femoris grafts and muscles. Compared with their respective donor muscles, 120 to 150 days after grafting, latissimus dorsi and rectus femoris grafts showed no change in the number of fibers and a decrease in the mean single-fiber cross-sectional area to approximately 70 percent. The latissimus dorsi grafts, which remained parallel-fibered, developed maximum forces 34 and 23 percent of the values for fully activated rectus femoris grafts and muscles, respectively. The deficit in the maximum force of the latissimus dorsi grafts resulted primarily from the smaller total-fiber cross-sectional area as a result of the parallel-fibered structure.

Anastomosis, Surgical↗

PubMed1992

An apparatus to measure in vivo biomechanical behavior of dorsi- and plantarflexors of mouse ankle.

We developed an apparatus to quantify the biomechanical behavior of the dorsi- and plantarflexor muscles of the ankle of an anesthetized mouse. When the dorsi- or plantarflexor muscle group is activated by electrical stimulation of either the peroneal or tibial nerve, the apparatus measures the moment developed about the ankle during isometric, isovelocity shortening, or isovelocity lengthening contractions. Displacements may be performed over the full 105 degrees range of ankle motion with an angular resolution of 0.09 degrees. Bidirectional isovelocity ramps in ankle angle up to 1,100 degrees/s are possible and are equivalent to maximum velocities of 2.3 fiber lengths/s (Lf/s) for the fibers in tibialis anterior muscle and 11.9 Lf/s for those in gastrocnemius muscle. During single contractions of the dorsi- and plantarflexor muscle groups at 37 degrees C and with both knee and ankle joint at 90 degrees neutral position, the isometric tetanic force developed was 1.4 and 3.3 N, power output at 2.2 Lf/s was 3.1 and 5.9 mW, and power absorption at 0.5 Lf/s was 4.9 and 9.0 mW, respectively. These values are in reasonable agreement with data from the same muscle groups tested in situ. We conclude that the apparatus provides valid measurements of force and power of the dorsi- and plantarflexor muscle groups.

Animals↗

PubMed1992

Aminophylline increases submaximum power but not intrinsic velocity of shortening of frog muscle.

We hypothesized that methylxanthines, such as aminophylline, increase the power developed by submaximally activated frog skeletal muscles by increasing the force developed at any given velocity of shortening. Frog semitendinosus muscles were excised and tested at 20 degrees C in oxygenated control and aminophylline Ringer solutions. Force-velocity relationships were determined and power was calculated from muscles stimulated at frequencies of 80 and 300 Hz. The 300-Hz frequency of stimulation produced a maximum rate of force development. In 50 and 500 microM aminophylline, twitch force increased by 25 +/- 12 and 75 +/- 13%, respectively. Aminophylline did not affect maximum isometric force generation or the shortening velocity at any relative load. At 80-Hz stimulation and in the presence of 500 microM aminophylline, power increased by an average of 11% at 10 of 14 relative loads. At maximum frequencies of stimulation, aminophylline had no effect on any measured parameter. We conclude that aminophylline increases the power developed by submaximally activated frog muscles through an increase in the force generated particularly at the lower velocities of shortening.

Aminophylline↗

PubMed1991

Maximum and sustained power of extensor digitorum longus muscles from young, adult, and old mice.

We tested the hypothesis that extensor digitorum longus (EDL) muscles in old mice would generate lower maximum powers and sustain lower powers than EDL muscles in young or adult mice. Power was measured in situ at 35 degrees C during single and repeated isovelocity shortening contractions through 10% of fiber length at optimum velocity for power. Sustained power was measured during repeated contractions at a stimulation frequency of 150 Hz. The train rate, and consequently the duty cycle, of repeated contractions was incremented every 5 to 10 min until force could not be maintained throughout the shortening contraction. During single contractions, the maximum absolute powers of muscles in young and old mice were 30% lower than that of adult mice, and power normalized by muscle mass (watts/kg) was 20% lower for muscles in old than for those in adult mice (p less than .05). During repeated contractions, EDL muscles in old and adult mice tolerated lower train rates and duty cycles and sustained lower absolute and normalized powers than EDL muscles in young mice.

Aging↗