Neutrophil accumulation following passive stretches contributes to adaptations that reduce contraction-induced skeletal muscle injury in mice.

Skeletal muscles can be injured by their own contractions, especially when the muscle is stretched during a lengthening contraction. Exposing a muscle to a conditioning protocol of stretches without activation (passive stretches) before lengthening contractions reduces contraction-induced injury. Although passive stretching does not damage muscle fibers, neutrophils are elevated in the muscle after passive stretches. Our purpose was to investigate the relationship between neutrophil accumulation following passive stretches and the protection from subsequent contraction-induced injury provided by the passive stretches. Our hypothesis was that passive stretch conditioning would not provide protection from subsequent lengthening contraction-induced injury under circumstances when the increase in muscle neutrophils in response to the conditioning was prevented. Extensor digitorum longus muscles of mice were conditioned with passive stretches 14 days before exposure to a protocol of damaging lengthening contractions. Mice were either untreated or treated with an antibody (RB6-8C5) that reduced the level of circulating neutrophils by over 95% before administration of passive stretches. Neutrophil levels recovered in treated mice by the time lengthening contractions were performed. Lengthening contractions were also administered to muscles with no prior exposure to passive stretches. Maximum isometric force, number of damaged fibers, and muscle neutrophil concentration were measured 3 days after lengthening contractions. Compared with nonconditioned control muscles, the severity of contraction-induced injury was not reduced by prior passive stretch conditioning when mice were treated with RB6-8C5 before conditioning. We conclude that neutrophils contribute to adaptations that protect muscles from injury.     

Muscle inflammatory cells after passive stretches, isometric contractions, and lengthening contractions.

We tested the hypotheses that lengthening contractions, isometric contractions, and passive stretches increase muscle inflammatory cells (neutrophils and macrophages) and that prior conditioning with lengthening contractions, isometric contractions, or passive stretches reduces neutrophils and macrophages after subsequent lengthening contractions. Extensor digitorum longus muscles in anesthetized mice were subjected in situ to lengthening contractions, isometric contractions, or passive stretches. Six hours or 3 days after a protocol of contractions or passive stretches, neutrophils and macrophages were quantified in muscle cross sections. Three days after isometric contractions or passive stretches, neutrophils were elevated (P < 0.05) 3.7- and 5.5-fold, respectively, relative to controls. Both macrophages and neutrophils were increased 51.2- and 7.9-fold, respectively, after lengthening contractions. Prior lengthening contractions, isometric contractions, or passive stretches reduced inflammatory cells after lengthening contractions performed 2 wk later. The major finding of this study was that passive stretches and isometric contractions elevated neutrophils without causing overt signs of injury. Because both passive stretches and isometric contractions elevated neutrophils and afforded some protection from contraction-induced muscle injury, neutrophils and/or the related inflammatory events may contribute to the induction of a protective mechanism.     

Severity of contraction-induced injury is affected by velocity only during stretches of large strain.

Our purpose was to investigate the effect of velocity of stretch on contraction-induced injury to whole skeletal muscles. Single stretches provide an effective method for studying factors that initiate contraction-induced injury. We tested the null hypothesis that the severity of injury is not dependent on the velocity of the stretch. From the plateau of maximum isometric contractions, extensor digitorum longus muscles of mice were administered single stretches in situ of 30--50% strain relative to muscle fiber length (L(f)) at rates of 1--16 L(f)/s. The magnitude of injury was represented by the isometric force deficit 1--10 min after the stretch. Although the null hypothesis was not supported because the force deficit was affected by velocity (r(2) = 0.09), the effect was relatively weak and was not significant except at the largest strain. Velocity had no effect on peak or average force or work input, factors established to have significant relationships with the force deficit. Velocity may play a minor role in contraction-induced injury, but its importance is negligible relative to that of strain.     

Branched fibers in dystrophic mdx muscle are associated with a loss of force following lengthening contractions

We demonstrated that the susceptibility of skeletal muscle to injury from lengthening contractions in the dystrophin-deficient mdx mouse is directly linked with the extent of fiber branching within the muscles and that both parameters increase as the mdx animal ages. We subjected isolated extensor digitorum longus muscles to a lengthening contraction protocol of 15% strain and measured the resulting drop in force production (force deficit). We also examined the morphology of individual muscle fibers. In mdx mice 1–2 mo of age, 17% of muscle fibers were branched, and the force deficit of 7% was not significantly different from that of age-matched littermate controls. In mdx mice 6–7 mo of age, 89% of muscle fibers were branched, and the force deficit of 58% was significantly higher than the 25% force deficit of age-matched littermate controls. These data demonstrated an association between the extent of branching and the greater vulnerability to contraction-induced injury in the older fast-twitch dystrophic muscle. Our findings demonstrate that fiber branching may play a role in the pathogenesis of muscular dystrophy in mdx mice, and this could affect the interpretation of previous studies involving lengthening contractions in this animal. skeletal muscle; mdx mouse; lengthening contraction; Duchenne muscular dystrophy     

Contraction-induced injury to single muscle fibers: velocity of stretch does not influence the force deficit

We tested the null hypothesis that theseverity of injury to single muscle fibers following a singlepliometric (lengthening) contraction is not dependent on the velocityof stretch. Each single permeabilized fiber obtained from extensordigitorum longus muscles of rats was maximally activated and thenexposed to a single stretch of either 5, 10, or 20% strain [%of fiber length (L_f)] ata velocity of 0.5, 1.0, or 2.0 L_f /s. Theforce deficit, the difference between maximum tetanic isometric force(P_o) before and after the stretch expressed as apercentage of the control value forP_o before the stretch, provided anestimate of the magnitude of muscle injury. Despite a fourfold rangefrom the lowest to the highest velocities, force deficits were notdifferent among stretches of the same strain. At stretches of 20%strain, even an eightfold range of velocities produced no difference inthe force deficit, although 40% of the fibers were torn apart at a velocity of 4 L_f /s. We conclude that, withinthe range of velocities tolerated by single permeabilized fibers, theseverity of contraction-induced injury is not related to the velocityof stretch.

     

Regeneration of new fibers in muscles of old rats reduces contraction-induced injury.

Skeletal muscles are injured by their own contractions. Compared with muscles in young animals, those in old animals are injured more easily and more severely and regenerate less well afterward. Injection of a myotoxin (bupivacaine) causes complete degeneration of fibers in extensor digitorum longus (EDL) muscles of rats, followed by full regeneration within 60 days. We tested the specific hypothesis that, 3 days after a protocol of pliometric (lengthening) contractions, the newly regenerated muscle fibers in bupivacaine-treated EDL muscles in both young and old rats would show a lesser deficit in maximum force and fewer damaged fibers than muscles in nontreated EDL muscles. The treated and nontreated EDL muscles of young and old male Wistar rats were administered a protocol of 225 pliometric contractions and were evaluated 3 days afterward, when morphological damage to muscle fibers is most severe. In treated compared with nontreated EDL muscles of both young and old rats, the force deficit and the number of damaged fibers were each reduced by approximately 75%. We conclude that newly regenerated fibers in muscles of young and old animals are resistant to injury and that maintenance of newly regenerated fibers by conditioning may prevent inadvertent damage, particularly in muscles of elderly people.     

Force deficits and breakage rates after single lengthening contractions of single fast fibers from unconditioned and conditioned muscles of young and old rats

The deficit in force generation is a measure of the magnitude of damage to sarcomeres caused by lengthening contractions of either single fibers or whole muscles. In addition, permeabilized single fibers may suffer breakages. Our goal was to understand the interaction between breakages and force deficits in "young" and "old" permeabilized single fibers from control muscles of young and old rats and "conditioned" fibers from muscles that completed a 6-wk program of in vivo lengthening contractions. Following single lengthening contractions of old-control fibers compared with young-control fibers, the twofold greater force deficits at a 10% strain support the concept of an age-related increase in the susceptibility of fibers to mechanical damage. In addition, the much higher breakage rates for old fibers at all strains tested indicate an increase with aging in the number of fibers at risk of being severely injured during any given stretch. Following the 6-wk program of lengthening contractions, young-conditioned fibers and old-conditioned fibers were not different with respect to force deficit or the frequency of breakages. A potential mechanism for the increased resistance to stretch-induced damage of old-conditioned fibers is that, through intracellular damage and subsequent degeneration and regeneration, weaker sarcomeres were replaced by stronger sarcomeres. These data indicate that, despite the association of high fiber breakage rates and large force deficits with aging, the detrimental characteristics of old fibers were improved by a conditioning program that altered both sarcomeric characteristics as well as the overall structural integrity of the fibers.     

Adaptive strength gains in dystrophic muscle exposed to repeated bouts of eccentric contraction

The objective of this study was to determine the functional recovery and adaptation of dystrophic muscle to multiple bouts of contraction-induced injury. Because lengthening (i.e., eccentric) contractions are extremely injurious for dystrophic muscle, it was considered that repeated bouts of such contractions would exacerbate the disease phenotype in mdx mice. Anterior crural muscles (tibialis anterior and extensor digitorum longus) and posterior crural muscles (gastrocnemius, soleus, and plantaris) from mdx mice performed one or five repeated bouts of 100 electrically stimulated eccentric contractions in vivo, and each bout was separated by 10-18 days. Functional recovery from one bout was achieved 7 days after injury, which was in contrast to a group of wild-type mice, which still showed a 25% decrement in electrically stimulated isometric torque at that time point. Across bouts there was no difference in the immediate loss of strength after repeated bouts of eccentric contractions for mdx mice (-70%, P = 0.68). However, after recovery from each bout, dystrophic muscle had greater torque-generating capacity such that isometric torque was increased ～38% for both anterior and posterior crural muscles at bout 5 compared with bout 1 (P < 0.001). Moreover, isolated extensor digitorum longus muscles excised from in vivo-tested hindlimbs 14-18 days after bout 5 had greater specific force than contralateral control muscles (12.2 vs. 10.4 N/cm(2), P = 0.005) and a 20% greater maximal relaxation rate (P = 0.049). Additional adaptations due to the multiple bouts of eccentric contractions included rapid recovery and/or sparing of contractile proteins, enhanced parvalbumin expression, and a decrease in fiber size variability. In conclusion, eccentric contractions are injurious to dystrophic skeletal muscle; however, the muscle recovers function rapidly and adapts to repeated bouts of eccentric contractions by improving strength.     

Importance of satellite cells in the strength recovery after eccentric contraction-induced muscle injury

The purpose of this study was to determine if the elimination of satellite cell proliferation using gamma-irradiation would inhibit normal force recovery after eccentric contraction-induced muscle injury. Adult female ICR mice were implanted with a stimulating nerve cuff on the common peroneal nerve and assigned to one of four groups: 1) irradiation- and eccentric contraction-induced injury, 2) eccentric contraction-induced injury only, 3) irradiation only, and 4) no intervention. Anterior crural muscles were irradiated with a dose of 2,500 rad and injured with 150 in vivo maximal eccentric contractions. Maximal isometric torque was determined weekly through 35 days postinjury. Immediately after injury, maximal isometric torque was reduced by approximately 50% and had returned to normal by 28 days postinjury in the nonirradiated injured mice. However, torque production of irradiated injured animals did not recover fully and was 25% less than that of injured nonirradiated mice 35 days postinjury. These data suggest that satellite cell proliferation is required for approximately half of the force recovery after eccentric contraction-induced injury.     

Characteristics of lengthening contractions associated with injury to skeletal muscle fibers

Lengthening (eccentric) contractions result in injury to skeletal muscle fibers. Two hypotheses were tested through lengthening contractions of an in situ muscle preparation: the extent of injury increases with increases in the duration; and the extent of injury increases with increases in the peak force. Mice were anesthetized, and distal tendons of the extensor digitorum longus muscles were attached to a servomotor. Muscles were stimulated at 150 Hz and lengthened 20% of fiber length (Lf). Lengthening contractions were performed at 0.2, 0.5, or 1.0 Lf/s with durations of 0.5-15 min. Peak force during lengthening contractions at 1.0 Lf/s was decreased by inducing fatigue with isometric contractions, stimulating at 70-100 Hz, or 3) lengthening 10% of Lf. Injury was assessed 3 days after lengthening contractions by histological appearance and maximum force (Po) development. Injury increased with duration up to 5 min. After 5 min, fatigue appeared to prevent further injury. Results for 0.2 and 0.5 Lf/s were similar to those for 1.0 Lf/s but with less injury. A high correlation was observed between histological appearance of injury and the decrease in Po. The extent of injury was related to the peak force developed during the lengthening contractions.     

Active force inhibition and stretch-induced force enhancement in frog muscle treated with BDM.

There is evidence that the stretch-induced residual force enhancement observed in skeletal muscles is associated with 1) cross-bridge dynamics and 2) an increase in passive force. The purpose of this study was to characterize the total and passive force enhancement and to evaluate whether these phenomena may be associated with a slow detachment of cross bridges. Single fibers from frog lumbrical muscles were placed at a length 20% longer than the plateau of the force-length relationship, and active and passive stretches (amplitudes of 5 and 10% of fiber length and at a speed of 40% fiber length/s) were performed. Experiments were conducted in Ringer solution and with the addition of 2, 5, and 10 mM of 2,3-butanedione monoxime (BDM), a cross-bridge inhibitor. The steady-state active and passive isometric forces after stretch of an activated fiber were higher than the corresponding forces measured after isometric contractions or passive stretches. BDM decreased the absolute isometric force and increased the total force enhancement in all conditions investigated. These results suggest that total force enhancement is directly associated with cross-bridge kinetics. Addition of 2 mM BDM did not change the passive force enhancement after 5 and 10% stretches. Addition of 5 and 10 mM did not change (5% stretches) or increased (10% stretches) the passive force enhancement. Increasing stretch amplitudes and increasing concentrations of BDM caused relaxation after stretch to be slower, and because passive force enhancement is increased at the greatest stretch amplitudes and the highest BDM concentrations, it appears that passive force enhancement may be related to slow-detaching cross bridges.     

Susceptibility to sarcomere injury induced by single stretches of maximally activated muscles of mdx mice.

The purpose was to investigate the contribution of mechanical damage to sarcomeres to the greater susceptibility of dystrophic muscle fibers to contraction-induced injury. Single stretches provide an effective method for studying mechanical factors that contribute to the initiation of contraction-induced injury. We hypothesized that, after single stretches, the deficits in isometric force would be greater for muscles of mdx than C57BL/10 mice, whereas membrane damage would be minimal for all muscles. Extensor digitorum longus (EDL) and soleus muscles of mice were removed under anesthesia with Avertin (tribromoethanol). During the plateau of a maximum isometric contraction in vitro, muscles were stretched through single strains of 20-60% fiber length. Isometric force was remeasured 1 min later, and muscles were then incubated in procion orange dye to identify fibers with membrane damage. Force deficits at 1 min were two- to threefold greater for EDL muscles of mdx compared with C57BL/10 mice, whereas no significant differences were observed between soleus muscles of mdx and C57BL/10 mice. For all muscles, membrane damage was minimal and not significantly increased by single stretches for either strain of mice. These data support a critical role of dystrophin maintaining sarcomere stability in EDL muscles, whereas soleus muscles retain abilities, in the absence of dystrophin, not different from control muscles to resist sarcomere damage.     

Exercise-induced injury to skeletal muscle

Strenuous or unaccustomed exercise can cause injury to skeletal muscle. This paper reviews our understanding of the mechanisms of exercise-induced injury. Measurements of exercise-induced injury have included muscle soreness, increased serum levels of intracellular enzymes, increased lysosomal enzyme activities, structural changes in muscle fibers, and prolonged decreases in force development that cannot be attributed to fatigue. Injury can be induced by exercise of small muscle groups, which suggests that it involves processes localized in skeletal muscles. Exercise of relatively short duration can result in injury, which indicates that long durations of exercise and associated metabolic changes are not necessary for injury to occur. Exercise that involves lengthening contractions results in greater evidence of muscle injury than exercise involving isometric or shortening contractions. Lengthening contractions are associated with higher levels of force and lower metabolic costs per muscle fiber than isometric or shortening contractions. These results suggest that changes in muscle metabolism are not responsible for exercise-induced injury to skeletal muscle. Exercise-induced injury is more likely the result of mechanical disruption of muscle fibers.     

Modulation of passive force in single skeletal muscle fibres

In this study, we investigated the effects of activation and stretch on the passive force-sarcomere length relationship in skeletal muscle. Single fibres from the lumbrical muscle of frogs were placed at varying sarcomere lengths on the descending limb of the force-sarcomere length relationship, and tetanic contractions, active stretches and passive stretches (amplitudes of ca 10% of fibre length at a speed of 40% fibre length/s) were performed. The passive forces following stretch of an activated fibre were higher than the forces measured after isometric contractions or after stretches of a passive fibre at the corresponding sarcomere length. This effect was more pronounced at increased sarcomere lengths, and the passive force-sarcomere length relationship following active stretch was shifted upwards on the force axis compared with the corresponding relationship obtained following isometric contractions or passive stretches. These results provide strong evidence for an increase in passive force that is mediated by a length-dependent combination of stretch and activation, while activation or stretch alone does not produce this effect. Based on these results and recently published findings of the effects of Ca2+ on titin stiffness, we propose that the observed increase in passive force is caused by the molecular spring titin.     

Voluntary activation level and muscle fiber recruitment of human quadriceps during lengthening contractions.

Voluntary activation levels during lengthening, isometric, and shortening contractions (angular velocity 60 degrees/s) were investigated by using electrical stimulation of the femoral nerve (triplet, 300 Hz) superimposed on maximal efforts. Recruitment of fiber populations was investigated by using the phosphocreatine-to-creatine ratio (PCr/Cr) of single characterized muscle fibers obtained from needle biopsies at rest and immediately after a series of 10 lengthening, isometric, and shortening contractions (1 s on/1 s off). Maximal voluntary torque was significantly higher during lengthening (270 +/- 55 N.m) compared with shortening contractions (199 +/- 47 N.m, P < 0.05) but was not different from isometric contractions (252 +/- 47 N.m). Isometric torque was higher than torque during shortening (P < 0.05). Voluntary activation level during maximal attempted lengthening contractions (79 +/- 8%) was significantly lower compared with isometric (93 +/- 5%) and shortening contractions (92 +/- 3%, P < 0.05). Mean PCr/Cr values of all fibers from all subjects at rest were 2.5 +/- 0.6, 2.0 +/- 0.7, and 2.0 +/- 0.7, respectively, for type I, IIa, and IIax fibers. After 10 contractions, the mean PCr/Cr values for grouped fiber populations (regardless of fiber type) were all significantly different from rest (1.3 +/- 0.2, 0.7 +/- 0.3, and 0.8 +/- 0.6 for lengthening, isometric, and shortening contractions, respectively; P < 0.05). The cumulative distributions of individual fiber populations after either contraction mode were significantly different from rest (P < 0.05). Curves after lengthening contractions were less shifted compared with curves from isometric and shortening contractions (P < 0.05), with a smaller shift for the type IIax compared with type I fibers in the lengthening contractions. The results indicate a reduced voluntary drive during lengthening contractions. PCr/Cr values of single fibers indicated a hierarchical order of recruitment of all fiber populations during maximal attempted lengthening contractions.     

Stretch-induced,steady-state force enhancement in single skeletal muscle fibers exceeds the isometric force at optimum fiber length

Stretch-induced force enhancement has been observed in a variety of muscle preparations and on structural levels ranging from single fibers to in vivo human muscles. It is a well-accepted property of skeletal muscle. However, the mechanism causing force enhancement has not been elucidated, although the sarcomere-length non-uniformity theory has received wide support. The purpose of this paper was to re-investigate stretch-induced force enhancement in frog single fibers by testing specific hypotheses arising from the sarcomere-length non-uniformity theory. Single fibers dissected from frog tibialis anterior (TA) and lumbricals (n=12 and 22, respectively) were mounted in an experimental chamber with physiological Ringer's solution (pH=7.5) between a force transducer and a servomotor length controller. The tetantic force-length relationship was determined. Isometric reference forces were determined at optimum length (corresponding to the maximal, active, isometric force), and at the initial and final lengths of the stretch experiments. Stretch experiments were performed on the descending limb of the force-length relationship after maximal tetanic force was reached. Stretches of 2.5-10% (TA) and 5-15% lumbricals of fiber length were performed at 0.1-1.5 fiber lengths/s. The stretch-induced, steady-state, active isometric force was always equal or greater than the purely isometric force at the muscle length from which the stretch was initiated. Moreover, for stretches of 5% fiber length or greater, and initiated near the optimum length of the fiber, the stretch-enhanced active force always exceeded the maximal active isometric force at optimum length. Finally, we observed a stretch-induced enhancement of passive force. We conclude from these results that the sarcomere length non-uniformity theory alone cannot explain the observed force enhancement, and that part of the force enhancement is associated with a passive force that is substantially greater after active compared to passive muscle stretch.     

Dihydropyridine and ryanodine receptor binding after eccentric contractions in mouse skeletal muscle.

The purpose of this study was to determine whether there are alterations in the dihydropyridine and/or ryanodine receptors that might explain the excitation-contraction uncoupling associated with eccentric contraction-induced skeletal muscle injury. The left anterior crural muscles (i.e., tibialis anterior, extensor digitorum longus, and extensor hallucis longus) of mice were injured in vivo by 150 eccentric contractions. Peak isometric tetanic torque of the anterior crural muscles was reduced approximately 45% immediately and 3 days after the eccentric contractions. Partial restoration of peak isometric tetanic and subtetanic forces of injured extensor digitorum longus muscles by 10 mM caffeine indicated the presence of excitation-contraction uncoupling. Scatchard analysis of [3H]ryanodine binding indicated that the number of ryanodine receptor binding sites was not altered immediately postinjury but decreased 16% 3 days later. Dihydropyridine receptor binding sites increased approximately 20% immediately after and were elevated to the same extent 3 days after the injury protocol. Muscle injury did not alter the sensitivity of either receptor. These data suggest that a loss or altered sensitivity of the dihydropyridine and ryanodine receptors does not contribute to the excitation-contraction uncoupling immediately after contraction-induced muscle injury. We also concluded that the loss in ryanodine receptors 3 days after injury is not the primary cause of excitation-contraction uncoupling at that time.     

Length-tension relationships are altered in regenerating muscles of the rat after bupivacaine injection.

Intramuscular injection of bupivacaine causes complete degeneration of fibers in extensor digitorum longus (EDL) muscles of rats, followed by complete regeneration within 60 days. Previous studies have shown that regenerated EDL muscles are protected from contraction-induced injury 60 days after bupivacaine injection. It is possible that these regenerated muscles have altered length-tension relations because of fiber remodeling. We tested the hypothesis that length-tension relations are different in bupivacaine-injected and noninjected control muscles. EDL and soleus muscles of the right hindlimb of deeply anesthetized rats were injected with bupivacaine and then allowed to recover for 7, 14, 21, or 60 days (7D, 14D, 21D, 60D), and isometric contractile properties were assessed. Muscles of the contralateral limb were not injected and served as control. EDL muscles recovered from bupivacaine injection more rapidly than soleus muscles, with mass restored to control levels at 21D, and isometric tetanic force (P(o)) restored to control at 60D. In contrast, mass and P(o) of injected soleus muscles was not restored to control even at 60D. In 7D EDL muscles, length-tension curves were shifted leftward compared with control, but in 21D and 60D EDL muscles length-tension curves were right shifted significantly (treatment x muscle length: P < 0.001). Although no clear shift in the position of the length-tension curve was observed in regenerating soleus muscles, force production was enhanced on the descending limb of the curve in 60D soleus muscles (treatment x relative muscle length: P < 0.01). The rightward shift in the length-tension curve of EDL muscles 60 days after bupivacaine injection is likely to contribute to the mechanism for their previously observed protection from contraction-induced injury.     

Rises in whole muscle passive tension of mammalian muscle after eccentric contractions at different lengths.

This is a report of experiments carried out on the medial gastrocnemius muscle of the anesthetized cat, investigating the effects of eccentric contractions carried out at different muscle lengths on the passive and active length-tension relationships. In one series of experiments, the motor supply to the muscle was divided into three approximately equal parts; in the other, whole muscles were used. Fifty eccentric contractions were carried out over different regions of the active length-tension curve for each partial or whole muscle. Active and passive length-tension curves were measured before and after the eccentric contractions. When eccentric contractions were carried out at longer lengths, there was a larger shift of the optimum length for active tension in the direction of longer muscle lengths and a larger fall in peak isometric tension. Passive tension was higher immediately after the eccentric contractions, and if the muscle was left undisturbed for 40 min, it increased further to higher values, particularly after contractions at longer lengths. A series of 20 passive stretches of the same speed and amplitude and covering the same length range as the active stretches, reduced the passive tension which redeveloped over a subsequent 40-min period. It is hypothesized that there are two factors influencing the level of passive tension in a muscle after a series of eccentric contractions. One is injury contractures in damaged muscle fibers tending to raise passive tension; the other is the presence of disrupted sarcomeres in series with still-functioning sarcomeres tending to reduce it.     

Systemic administration of IGF-I enhances oxidative status and reduces contraction-induced injury in skeletal muscles of mdx dystrophic mice

The absence of dystrophin and resultant disruption of the dystrophin glycoprotein complex renders skeletal muscles of dystrophic patients and dystrophic mdx mice susceptible to contraction-induced injury. Strategies to reduce contraction-induced injury are of critical importance, because this mode of damage contributes to the etiology of myofiber breakdown in the dystrophic pathology. Transgenic overexpression of insulin-like growth factor-I (IGF-I) causes myofiber hypertrophy, increases force production, and can improve the dystrophic pathology in mdx mice. In contrast, the predominant effect of continuous exogenous administration of IGF-I to mdx mice at a low dose (1.0-1.5 mg.kg(-1).day(-1)) is a shift in muscle phenotype from fast glycolytic toward a more oxidative, fatigue-resistant, slow muscle without alterations in myofiber cross-sectional area, muscle mass, or maximum force-producing capacity. We found that exogenous administration of IGF-I to mdx mice increased myofiber succinate dehydrogenase activity, shifted the overall myosin heavy chain isoform composition toward a slower phenotype, and, most importantly, reduced contraction-induced damage in tibialis anterior muscles. The deficit in force-producing capacity after two damaging lengthening contractions was reduced significantly in tibialis anterior muscles of IGF-I-treated (53 +/- 4%) compared with untreated mdx mice (70 +/- 5%, P < 0.05). The results provide further evidence that IGF-I administration can enhance the functional properties of dystrophic skeletal muscle and, compared with results in transgenic mice or virus-mediated overexpression, highlight the disparities in different models of endocrine factor delivery.