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Ann Thorac Surg 1998;66:1983-1990
© 1998 The Society of Thoracic Surgeons

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Original Articles

Activity–rest stimulation of latissimus dorsi for cardiomyoplasty: 1-year results in sheep

^a Cardiovascular Surgery, The S. Orsola Hospital, University of Bologna, Bologna, Italy
^b C.N.R. Unit for Muscle Biology and Physiopathology and Department of Biomedical Sciences, University of Padova, Padova, Italy

Accepted for publication June 3, 1998.

Address reprint requests to Dr Carraro, Department of Biomedical Sciences, University of Padova, Viale Colombo, 3, I-35121 Padova, Italy

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. In dynamic cardiomyoplasty electrostimulation achieves full transformation of the latissimus dorsi (LD); therefore, its slowness limits the systolic support. Daily activity–rest could maintain partial transformation of the LD.

Methods. Sheep LD were burst-stimulated either 10 or 24 hours/day. Before and 2, 4, 6, and 12 months after stimulation, LD power output, fatigue resistance, and tetanic fusion frequency were assessed. Latissimus dorsi were biopsied at 6 months, and sheep sacrificed at 12 months.

Results. After 1 year of 10 hours/day stimulation LD was substantially conserved and contained large amounts of fast type myosin. From 2 months to 1 year of stimulation the power per muscle of the daily rested LD was greater than that of the left ventricle, being three to four times higher than in the 24-hour/day stimulation.

Conclusions. If extended to humans, these results could be the rationale for the need of a cardiomyostimulator, whose discontinuous activity could offer to patients the long-standing advantage of a faster and powerful muscle contraction.

	Introduction

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Experiments in sheep, aimed at investigating the use of latissimus dorsi (LD) as an energy source for a skeletal muscle ventricle, allowed us to conclude that the power generated by a fully conditioned LD could provide no better than partial assistance for a failing heart [1–3]. On the other hand, those results are useful for a critical evaluation of the power of the LD in dynamic cardiomyoplasty, a procedure in which the patient’s own left LD is wrapped circumferentially around the failing heart, conditioned and stimulated to augment cardiac contractility [4, 5].

The limiting factors of LD–heart interactions in cardiomyoplasty are (1) loss of resting tension attributable to LD mobilization; (2) circumferential wrapping around the failing heart; and (3) muscle performance after full conditioning. Both the mobilization of the muscle and the need not to interfere with heart diastole reduce LD resting tension, thereby decreasing its work potential. Latissimus dorsi may contribute to the hemodynamic work of the heart if its power is at least equal to the instant power of the ventricle during its own contraction–relaxation cycle. In cardiomyoplasty only a portion of the LD is circumferentially wrapped around the heart, and because, according to Laplace’s law, by doubling the radius of the heart the muscle mass must be four times greater to maintain the same pressure, it is conceivable that in the dilated heart the contribution of a fully conditioned muscle to systolic work is difficult to demonstrate by beat-to-beat analysis [6].

After a few weeks of chronic stimulation, LD mitochondrial content and capillary/myofiber ratio increase, but intracellular calcium handling becomes less efficient and, therefore, the contraction–relaxation cycle significantly slows; finally slow myosin substitutes for fast myosins, and thus a fast, powerful anaerobic (but early fatiguable) LD is transformed into an aerobic slow contracting muscle that is fatigue resistant at moderate power [7].

Because maximum instant power of a fully conditioned LD is smaller than the peak power of the left ventricle [1–3], we suggest that the grafted muscle could assist the heart only during late end-systole, just before closure of the aortic valve. Of course, such a short window asks for a fast, powerful contraction that is not delivered by a fully transformed LD. Therefore, we reevaluated the concept of "muscle conditioning" and its goal in cardiomyoplasty.

Actual clinical protocol makes the LD very resistant to fatigue, but meanwhile its dynamic characteristics are suboptimal; with a stimulation train of six impulses, the contraction–relaxation cycle of a fully conditioned LD could last longer than the heart systole [10].

We are testing whether an intermediate state of muscle transformation could be maintained long term, to have the advantages of a fatigue-resistant muscle that maintains fast dynamic contractile characteristics. We present 1-year results of a pilot study based on the hypothesis that resting the LD several hours per day allows it to maintain an intermediate state of transformation as a result of the daily training–detraining effect. Furthermore, a daily intermittent stimulation of the LD could also be less detrimental for the muscle tissue as such a protocol gives the muscle time to recover in between activity periods.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Surgical procedures and analyses of dynamic characteristics of sheep LD were performed at the Experimental Surgery Unit, The S. Orsola Hospital, University of Bologna; gross anatomy and histochemical and molecular analyses on muscle specimens were accomplished at the Department of Biomedical Sciences, University of Padova. After a series of preliminary experiments the pilot study was conducted in six adult sheep. Animals received proper care in compliance with "Guide for the Care and Use of Laboratory Animals" formulated by the National Academy of Science and published by the National Institutes of Health (NIH publication 85-23, revised 1985). Sheep were medicated with intramuscular ketamine (10 mg/kg) and diazepam (0.5 mg/kg), then anesthetized with 2% isoflurane. During operation, animals were ventilated with 400 mL of 88% oxygen per breath at a rate of 12 cycles/min; body temperature, blood pressure, and electrocardiogram were monitored. Operation was accomplished using sterile procedure. To mimic flap transposition effects of cardiomyoplasty, which result in LD distal devascularization and decreased resting tension, an incision was made that extended along the lateral and posterior borders from the axillary fold to the costal margin of the 11th rib and the LD. The incision along the aponeurosis origin completely dissected the experimental muscle from the surrounding tissue, therefore all the vessels were sacrificed (one to three major collateral blood vessels). As indicated in Figure 1, from its natural insertions to ribs and spinal column (interrupted line) the LD was resutured to ribs in the shortened position it spontaneously attained. ITREL stimulator (Medtronic, Minneapolis, MN) and intramuscular electrodes were implanted according to the Medtronic protocol [3], and the skin was sutured.

View larger version (50K): [in this window] [in a new window]   Fig 1. Cardiomyoplasty-like mobilization of sheep latissimus dorsi and daily continuous or activity–rest stimulation. From its natural insertions to ribs and spinal column (interrupted line) the latissimus dorsi was resutured to ribs in the shortened position it spontaneously attained.

To allow repetitive measurements of the contractile characteristics of the shortened LD in the same sheep, the leg but not the muscle tendon was secured to a force transducer. Because in these conditions isometric tests could not be performed at optimal muscle length, tetanic fusion frequency was used as an index of duration of the contraction–relaxation cycle of the surgically shortened LD. Then stimulators were programmed to settings that just elicited fatiguing contractions in the shortened LD. Four sheep were stimulated 10 hours/day, and two sheep were stimulated 24 hours/day. In both cases LD was stimulated about 30 times per minute with bursts of three impulses lasting about 140 ms at 20 Hz.

Tetanic fusion frequency, fatigue tests, and power output were reassessed after 2, 4, 6, and 12 months of stimulation. Because fatigue appeared just above the conditioning settings (but of course at higher sustained power outputs), stimulation parameters were not changed during the experiment. In sheep stimulated 24 hours/day stimulation was suspended after 6 months when biopsies were taken from the distal part of all the experimental LD muscles. At 12 months the sheep were sacrificed by excessive anesthesia. The LD were dissected, perimysial fat and connective tissue carefully removed, and the muscles weighed and photographed. Three muscle specimens were cut out from proximal, intermediate, and distal portions of the LD, quenched in liquid nitrogen and stored at -80°C until use.

Morphometry of myofibers and interstitial tissue, myosin ATPase, and isomyosin profile by sodium dodecyl sulfate–polyacrylamide gel electrophoresis of the myosin heavy chains were performed as described by Rizzi and colleagues [11] on serial cryostat sections of the 12-month specimens and on distal biopsies performed only after 6 months of stimulation to limit the surgical muscle damage during the experiment [3]. Molecular markers of muscle damage/repair/regeneration (contents of total lipids, total protein, myosin/actin ratio, and sodium dodecyl sulfate–polyacrylamide gel electrophoresis of myosin heavy chains) were determined in whole muscle homogenate of each experimental LD [11].

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Figure 2 shows the gross anatomy of experimental muscles removed after 12 months of 10-hour/day stimulation or 6 months of 24-hour/day stimulation followed by a 6-month rest. The largest muscles are the contralateral normal LD (Fig 2B, D), and the muscles in Figure 2A, C, E, and F are the LD muscles stimulated for 12 months for 10 hours/day; although slightly diminished in size and weight the chronically stimulated muscle appears trophic and as red as the normal muscle. The muscles in Figure 2G and H are sheep LD that had been stimulated for 6 months for 24 hours/day and then rested for additional 6 months; they appear pale and fibrotic. In Figure 2I the cross section of the muscles demonstrate the differential content of fat and fibrotic tissue in the different experimental muscles. Table 1, which shows wet weight, content of contractile and soluble proteins, and the fat of the contralateral and experimental muscles, confirms the differential effects of half-day and daily LD stimulation. Muscles stimulated for 12 months for 10 hours/day show only about 10% atrophy in comparison with normal contralaterals, whereas the LD stimulated for 6 months for 24 hours/day and then rested for an additional 6 months present about 40% atrophy.

View larger version (44K): [in this window] [in a new window]   Fig 2. Cardiomyoplasty-like mobilization of sheep latissimus dorsi and daily continuous or activity–rest stimulation. Anatomic records. Normal latissimus dorsi from sheep: (B) 5/95; (D) 6/95; latissimus dorsi after 12 months of 10-hour/day-stimulation from sheep: (A) 5/95; (C) 6/95; (E) 4/95; (F) 1/95; latissimus dorsi after 6 months of 24-hour/day stimulation followed by a 6-month rest: (G) 2/95; (H) 3/95. (I) Cross section of the muscles. Although slightly diminished in size and weight, after 1 year of daily activity–rest stimulation the latissimus dorsi appear trophic and as red as the normal contralateral muscles.

View larger version (124K): [in this window] [in a new window]   Fig 3. Cardiomyoplasty-like mobilization of sheep latissimus dorsi and daily continuous or activity–rest stimulation. Hematoxylin and eosin stain (A, C, E) and pH 4.35 ATPase (B, D, F) of distal samples of latissimus dorsi. Six months of 24-hour/day stimulation: (A) sheep 2/95 (hematoxylin and eosin); (B) sheep 2/95 (ATPase); 6 months of 10-hour/day stimulation: (C) sheep 6/95 (hematoxylin and eosin); (D) sheep 6/95 (ATPase); (E) normal ATPase latissimus dorsi (hematoxylin and eosin); (F) normal latissimus dorsi (ATPase). (Hematoxylin and eosin; x100 before 14% reduction, ATPase; x80 before 14% reduction.)

View larger version (101K): [in this window] [in a new window]   Fig 4. Cardiomyoplasty-like mobilization of sheep latissimus dorsi and daily continuous or activity–rest stimulation. (Hematoxylin and eosin; x100 before 8% reduction.) Distal samples of sheep latissimus dorsi after 6 months of 24-hour/day stimulation followed by 6 months of rest: (A) sheep 2/95; (B) sheep 3/95; latissimus dorsi after 12 months of 10-hour/day stimulation: (C) sheep 1/95; (D) sheep 4/95; (E) sheep 5/95; (F) sheep 6/95.

View larger version (125K): [in this window] [in a new window]   Fig 5. Cardiomyoplasty-like mobilization of sheep latissimus dorsi and daily continuous or activity–rest stimulation. (ATPase pH 10.4 x80 before 14% reduction.) Distal samples of latissimus dorsi after 6 months of 24-hour/day stimulation followed by 6 months of rest: (A) sheep 2/95; (B) sheep 3/95; latissimus dorsi after 12 months of 10-hour/day stimulation: (C) sheep 1/95; (D) sheep 4/95; (E) sheep 5/95; (F) sheep 6/95.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

Previous experiments that we performed in a series of sheep to investigate the use of LD as an energy source for a skeletal muscle ventricle allowed us to conclude that the power generated by a fully conditioned LD could provide no better than partial assistance for a failing heart [1–3]. On the other hand, those results are useful for a critical evaluation of the energetic contribution of the LD to dynamic cardiomyoplasty [4, 5]. To many investigators, cardiomyoplasty is a clinical reality, whose basis is founded more on a girdle effect that limits or even reverses the progressive dilatation of a failing heart, than on an active systolic assist; indeed a very critical approach is needed to demonstrate beat-to-beat assistance. On the other hand, load-independent measurements demonstrate a real amelioration of the heart energetic when analyses are compared before and after cardiomyoplasty [6].

The factors that limit LD–heart interactions in cardiomyoplasty are (1) loss of resting tension due to LD mobilization; (2) circumferential wrapping around the failing heart; and (3) muscle performance after full conditioning. Both the mobilization of the muscle and the need not to interfere with heart diastole reduce LD resting tension, thereby decreasing its work potential.

The LD may contribute to hemodynamic work of the heart if its power is equal to the instant power of the ventricle during its own contraction–relaxation cycle. In cardiomyoplasty only a portion of LD is circumferentially wrapped around the heart, and using Laplace’s law doubling the radius of the heart, the muscle mass must be four times greater to maintain the same pressure. It is conceivable that in dilated heart the contribution of a fully conditioned muscle to systolic work is difficult to demonstrate by beat-to-beat analysis.

After a few weeks of chronic stimulation, LD mitochondrial content and capillary-to-myofiber ratio increase, but intracellular calcium handling becomes less efficient and therefore, the contraction–relaxation cycle significantly slows; finally slow myosins substitute for fast myosins, thereby a fast, powerful anaerobic (but early fatiguable) LD is transformed into an aerobic slow-contracting muscle that is fatigue resistant at moderate power [7]. Because the heart delivers 1.3 W of power to maintain basal metabolism, altogether the above mentioned factors explain why the systolic contribution of a fully transformed LD is low in cardiomyoplasty [8].

Clinically, the LD benefits the patient’s quality of life only if its activation is critically delayed after sensed QRS to avoid mitral regurgitation [9]. Because maximum instant power of a fully conditioned LD is smaller than the peak power of the left ventricle [1–3], we suggest that the grafted muscle could assist the heart only during late end-systole, just before closure of the aortic valve. Of course, such a small window demands a fast, powerful contraction that is not delivered by a fully transformed LD. Therefore, we reevaluated the concept of "muscle conditioning" and its goal in cardiomyoplasty.

Actual clinical protocol makes the LD very resistant to fatigue, but its dynamic characteristics are suboptimal. Indeed with a 160-ms stimulation train of six impulses (six impulses delivered every 32 ms), the contraction–relaxation cycle of a conditioned LD could last longer than the heart systole [10]. We are testing whether an intermediate state of muscle transformation could be maintained long term to better sustain faster contractions (cardiac-like amount of averaged external power, >1 W of power per LD).

Previously [3] we showed that after shortening but before conditioning the sheep LD was able to deliver about 0.1 W of extracted power by stimulating it with single impulses at 2 Hz (120 events/minute), which is the higher frequency of a heart pacemaker. Of course when tetanic contractions were elicited by bursts of impulses, the shortened LD delivered 0.2 to 0.3 W of external power without signs of fatigue. After increasing the frequency of tetani or inducing more powerful tetani by bursts at higher frequency, the external power reached 0.5 to 1.0 W per muscle, but the muscles fatigued in a few minutes and then external power either leveled off at about 0.2 W per muscle, or even ceased when workloads were maintained near maximal values. An implication of our observations is that after cardiomyoplasty LD could deliver sustainable power immediately after the healing period by setting the stimulator at very low muscle demands [3].

After chronic stimulation the working capacity of the LD increases, but only if the LD is rested several hours every day when the sustained power exceeds the value of the left ventricle at rest, as it seems possible to maintain an intermediate state of myofiber transformation in the sheep LD by a daily activity–rest regimen.

The biological basis of such an approach is that "intermediate" myofibers do exist in nature; several different types of myofibers with intermediate characteristics between very fast and very slow contracting fibers exist in skeletal muscles of mammals, humans included, their characteristics being induced and maintained by different levels of activity against load [7]. By imposing the proper workload, it is possible to regulate gene expression and to transform all the fibers to a desired type.

To allow repetitive measurements of the contractile characteristics of the shortened LD in the same sheep, the leg but not the muscle tendon was secured to the force transducer. Because under these conditions isometric tests could not be performed at optimal muscle length, tetanic fusion frequency was used as an index of duration of the contraction–relaxation cycle of the shortened LD. As the values are lower than those expected for sheep LD under optimal length [3], we have indirect evidence that the LD are really shortened by our procedure.

Furthermore, it is worth stressing that after 6 months of stimulation the frequency of tetanic fusion was higher (ie, the contraction–relaxation cycle was faster) in the 10-hour/day than in the 24-hour/day stimulated LD, and that this difference disappeared at 1 year as the fusion frequency of the 6-month rested muscle recovered to values of the 1-year 10-hour/day stimulated LD. Although demonstrated under suboptimal conditions, changes in frequency of tetanic fusion are evidence of a training–detraining effect of our stimulation regimen.

Convincing results are collected by analysis of isomyosins in the experimental muscles. Analyses of myosin heavy chain isoforms by sodium dodecyl sulfate–polyacrylamide gel electrophoresis in serial sections of muscle biopsies taken 6 months after stimulation showed that the 24-hour/day stimulated LD contain only myosin heavy chain 1 (ie, they are fully transformed), whereas the muscles stimulated 10 hours/day still contain large amounts of fast type myosin heavy chain, in particular type 2A. Furthermore we show that after 12 months of stimulation, the 10-hour/day stimulated LD contain substantial amounts of fast type myosin heavy chains, and that after 6 months of resting the fast-type myosin heavy chain are reexpressed in the 24-hour/day stimulated LD. These observations explain the different dynamic characteristics of the two groups of LD, as calcium uptake/release is faster in type 2A than in type 1 myofibers.

At 6-month stimulation, frequency of tetanic fusion was higher in 10-hour/day stimulated muscles than in LD fully conditioned by electrostimulation for 24 hours/day. At 1 year the contraction–relaxation cycle of the 10-hour/day stimulated LD is as fast as at 6 months. The 6-month discontinued stimulation retrodifferentiates the LD, which was fully transformed by 6 months of 24-hour/day activity. Interestingly the complement of myosin heavy chains is very similar in the two groups of muscles, suggesting that the total amount of muscle contractions have a main role in driving gene expression in the myofibers. These results are in full agreement with results of long-term training and detraining experiments in rodents, rabbit, goat, sheep, and humans [2, 7, 12–14].

Comparison between various regimens of stimulation, such as daily amount of treatment or frequency, are rare. It is likely that 10 hours of stimulation per day will produce different results than 24 hours/day. First, 10 hours of stimulation cover about one-third of the 24-hour stimulation period and, second, this protocol gives the muscle time to recover in between. Although the possibility exists that final outcome of changes using either method may be, ultimately, similar after long-term periods of stimulation (ie, after several years), it is well established that in animals stimulated 12 hours/day, mRNA of myosin heavy chain 1 becomes detectable when stimulation periods exceed 20 days, whereas continuous stimulation (24 hours/day) leads to an earlier appearance of the mRNA (9 days). Furthermore, cessation of stimulation has pronounced effects on the mRNA pattern leading to a rapid reversal (hours) of the stimulation-induced changes [3].

Biochemical changes (eg, acidosis, AMP, inorganic phosphate that accumulate during muscle fatigue, or cytosolic calcium) are probably the intracellular messengers of muscle plasticity. The actual clinical stimulation protocol of cardiomyoplasty is very demanding, therefore it is not surprising that the LD is transformed in a pure slow-type muscle by long-term continuous stimulation. Indeed either 9 months or 2 years after cardiomyoplasty histochemical analyses revealed only type 1 fibers in the LD flap stimulated every cardiac cycle with 30-Hz bursts lasting 160 ms [13].

In summary, it is conceivable that in our pilot experiment in sheep an intermediate state of LD transformation is maintained at least up to 1 year by daily modulation of the working periods.

A second issue in dynamic cardiomyoplasty is whether muscle damage is induced by the chronic abnormal stimulation, in particular when a muscle-to-heart contraction ratio of 1:1 is applied. Exercise may induce muscle damage, and physiologists, sports scientists, and physiatrists are well aware that spontaneous exercise per se could be a trauma to muscle fibers [15, 16]. Cardiomyoplasty is a complex procedure and it is difficult to even identify the relevant variables [2, 3, 14]. Because the controlled environments of a physiologist’s experiment are not applicable, we have variable results in our few sheep.

In any case the biopsies of 10-hour/day stimulated LD present a well-preserved muscle structure with moderate and nonspecific changes; myofiber size is much larger and interstitial tissue is smaller than in biopsies of all-day-stimulated LD. This result is in agreement with data previously reported on goat LD surgically dissected and stimulated for 2 months either 24 hours/day or 16 hours/day [14], and long-term studies in rabbit and rodents whose continuous stimulation is known to decrease the surface-to-diameter and muscle mass-to-blood perfusion ratios to favor oxidative metabolism of the myofibers [12]. If the muscle is rested daily homeostasis seems to be near normal values. Indeed after 1 year of 10-hour/day stimulation wet weight of muscle is only 10% lower than that of normal contralateral LD, whereas the LD stimulated 6 months for 24 hours/day and then rested for 6 months shows a 40% decrease in wet weight.

Taking into account the fat and collagen content in the muscles, it is evident that gross anatomy underestimates the extent of ongoing damage in chronically stimulated muscles. Results of the histologic analyses performed on biopsies taken after 6 months of stimulation strongly suggest that the decreased weight of the LD stimulated for 6 months for 24 hours/day and then rested for an additional 6 months is more likely the consequence of the 6 months of daily stimulation than of the 6 months of rest. Indeed the myofibers of those LD were atrophic and the tissue was heavily infiltrated by fat and connective tissue after 6 months of 24 hours/day of stimulation [3]. Furthermore, although shortened, the LD are properly innervated and therefore possibly activated by standing and walking activity as with the normal contralateral LD.

On the other hand, the true question is whether the unusual work performed in cardiomyoplasty by the graft damages human LD. There are reports explaining long-term ceased effect of the procedure with indirect evidence of major muscle atrophy, fibrosis, and fat infiltration; furthermore, direct histologic evidence of muscle damage had been collected in sheep and goat experiments [9, 14, 17]. On the contrary, two autoptic cases directly show that this is not an obligatory event; 15 months or even 8 years after cardiomyoplasty morphologic and molecular analyses of the pedicled LD showed preserved muscle mass and patent vessels with normal endothelial and smooth muscle walls. Interestingly, in these two cases LD graft was activated every second or fourth sensed QRS, and clinical results were excellent [18].

Several independent factors may damage the muscle besides the pattern of activation (ie, lesions of nerves, arteries, or veins during or after operation, loss of resting tension) [10, 14]. Histopathologic observations of grafted LD up to 8 years after cardiomyoplasty demonstrate that damage is not a mandatory consequence of the unusual activity the muscle performs to assist the failing heart [18].

Eleven years after the first clinical case, we may hope that cardiomyoplasty is at the stage heart transplantation was after immunopharmacologists solved the problem of rejection of autologous transplant by immunosuppressive drugs, which are now accepted clinical practice. Also in heart transplantation, the surgical problems were solved several years earlier than the rejection problem. Carpentier and Chachques [4] established the basic surgical procedure 12 years ago; now the knowledge exists to overcome some of the remaining problems of cardiomyoplasty. Several investigators are collecting scientific evidence on the mechanisms and effectiveness of cardiomyoplasty [6, 9]. Risks of "damage" of LD may be reduced and muscle performance increased by (1) using pre- and post-cardiomyoplasty different work–rest stimulation regimens; (2) testing nerve versus intramuscular electrostimulation; (3) optimizing the surgical procedure; and (4) administrating local anabolic agents to the LD flap [2, 3, 19].

We are confident that our pilot experiment will attract attention, and reinforcing the concept of a lighter and demand stimulation of the grafted LD, it will contribute to a larger acceptance of the procedure, to a better management of pharmacologically intractable heart failure with an acceptable quality of life for the subjects. Preliminary results in patients are more than encouraging [20].

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
This study was supported by the Italian Ministero Università e Ricerca Scientifica e Tecnologica (MURST) funds to Giorgio Arpesella and in part by funds from the Italian Consiglio Nazionale delle Ricerche (CNR) to the Unit for Muscle Biology and Physiopathology, and MURST to Ugo Carraro. The financial support of TELETHON—ITALY to the project "Role of apoptosis of myofibers, satellite cells and endothelia in exercise-induced muscle damage and in progression of muscular dystrophies (n. 968)" is gratefully acknowledged.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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