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PubMed1996

Structural muscle damage and muscle strength after incremental number of isometric and forced lengthening contractions.

Exercise-induced muscle damage is characterized by histological changes, like Z-line streaming, inflammatory response and decreased muscle function reflected in a prolonged decline in maximal isometric muscle strength after eccentric work. It is assumed that force decrement is mainly related to the amount of structural damage. However, the relationship between number of eccentric contractions, magnitude of structural damage and force decrement is not very well documented. Therefore we studied the effect of an increasing number of both isometric and eccentric (forced lengthening) contractions on histological parameters of muscle damage and maximal isometric force in an experimental in situ rat model. Tibialis anterior muscles of male Wistar rats were subjected to an increasing number of either isometric or eccentric contractions and were examined for histological markers of muscle damage. The present study shows that muscle damage increases progressively with the number of forced lengthening contractions. Maximal isometric torque was found to decline after both types of exercise. However, the decline after forced lengthening exercise was more pronounced. Only a weak relationship between percentage of histological muscle damage and isometric torque after forced lengthening contractions was found. The findings of the present study suggest that the decline in muscle force after eccentric exercise may partly be attributed to other factors than structural damage.

Analysis of Variance↗

PubMed1988

Myogenic and neurogenic regulation of myosin gene expression in cat jaw-closing muscles regenerating in fast and slow limb muscle beds.

Immunocytochemical techniques were used to study changes in myosin gene expression during the regeneration of the cat posterior temporalis muscle transplanted into the bed of either the fast extensor digitorum longus (EDL) or the slow soleus muscle. Strips of the posterior temporalis, a homogeneously superfast muscle, were treated with Marcaine and then transplanted into limb muscle beds which had been completely cleared of host muscle fibres. The regenerates were examined 6 to 224 days after surgery. Early regenerates in both muscle beds reacted with antibodies against the heavy chain of foetal, slow and superfast myosins, but not with antibodies against fast myosin. In the long-term, regenerates innervated by the EDL nerve expressed only superfast myosin whereas in the regenerates innervated by the soleus nerve most fibres expressed only slow myosin and only a few fibres reacted exclusively with the anti-superfast myosin antibody even after 210 days. In contrast, EDL and soleus muscles regenerating in their own beds expressed foetal, slow and fast myosin, but did not express superfast myosin. The isometric contraction times of the various types of regenerates reflected the types of myosin synthesized. It is concluded that jaw and limb muscle cells exist as two distinct allotypes, each having a distinct repertoire for the expression of adult isomyosins, and that within that repertoire isomyosin gene expression can be modulated by the nerve. Thus, myosin gene expression in skeletal muscle fibres is regulated by both myogenic and neurogenic mechanisms.

Animals↗

PubMed1989

Size and charge heterogeneity of C-protein isoforms in avian skeletal muscle. Expression of six different isoforms in chicken muscle.

C-protein is an abundant protein, of unknown function, found in the striated muscles of all vertebrates (Offer et al., 1973). Based on differences in size, charge, antigenicity and sarcomere distribution, at least three different isoforms of this protein have been identified (Callaway & Bechtel, 1981; Yamamoto & Moos, 1983; Reinach et al., 1982; Dhoot et al., 1985). These have been termed fast-, slow- and cardiac-type isoforms, relative to their distribution in adult striated muscles. Each of these isoforms appears to be expressed sequentially during the development of the chicken pectoralis muscle (Obinata et al., 1984; Obinata, 1985). To better characterize the various isoforms of C-protein, we have reexamined its in vivo expression during avian myogenesis using a combination of 1- and 2-dimensional gel electrophoresis, cell-free translation and immunoblotting procedures. In this manuscript we demonstrate for the first time that at least four major C-protein isoforms can be distinguished in adult chicken muscles. These include a fast-type isoform in the pectoralis (PECT) muscle (Cf), a slow-type isoform in the anterior latissimus dorsi (ALD) muscle (Cs3), a second slow-type isoform in the posterior latissimus dorsi (PLD) muscle (Cs4) and a cardiac-type in the ventricle (Cc). During embryonic development of the PECT muscle two additional isoforms can be resolved. These are both slow-type isoforms based on their reactivities with ALD66, a monoclonal antibody specific for adult slow-type C-protein. These latter isoforms have been termed Cs1 and Cs2. Several of the isoforms, particularly Cs1 ands Cs3, exhibit two or more spots of different charge but identical molecular weight on 2-D gels. This observation suggests the possibility that these isoforms are post-translationally modified and possibly phosphorylated. Our data show the C-protein family in avian striated muscles to be highly complex. Additional genetic analyses and primary sequence studies will be required to distinguish transcriptional from post-transcriptional variants.

Animals↗

PubMed2002

Comparison between the effects of chronic and acute hypoxemia on muscle afferent activities from the tibialis anterior muscle.

The reflex loops initiated by the activation of muscle afferents are altered by a reduction of the oxygen supply. This has been shown in different mammalian species under experimental conditions of acute or chronic hypoxemia. In the present study in rats, we compared the effects of acute and chronic hypoxemia on the activity of afferents from the tibialis anterior muscle to investigate the existence of possible adaptive mechanisms to hypoxaemia. The activity in groups I and II (mechanosensitive) and groups III and IV (mechano- and mostly chemosensitive) muscle afferents was recorded under conditions of normoxaemia and acute and chronic hypoxemia. Chronic hypoxaemia was achieved by exposing the rats for 45 consecutive days to a gas mixture containing 10% oxygen in nitrogen, whereas acute hypoxaemia was limited to a 1-h exposure to a 10% oxygen mixture. Different test agents: muscle stimulation (MS), arterial injection of KCl or lactic acid and tendon vibrations, were used to activate muscle afferents. Both acute and chronic hypoxaemia suppressed the post-MS activation of groups III and IV muscle afferents and significantly depressed the response of these afferents to KCl and lactic acid. The pattern of response of mechanosensitive afferents to mechanical tendon vibration was similar under the three conditions but chronic hypoxemia significantly reduced the response to 10-50 Hz vibrations. We conclude that inhibitory effects on muscle metabosensitive afferents occurred in the first minutes following acute hypoxemia and was prolonged with chronic hypoxemia. Our data also suggest that chronic hypoxemia depresses mechanosensitive muscle afferents. This may explain the observation that sensorimotor control of skeletal muscles is often markedly impaired in hypoxemic humans.

Action Potentials↗

PubMed1998

Experimental jaw-muscle pain does not change heteronymous H-reflexes in the human temporalis muscle.

Muscle pain generally has an inhibitory effect on voluntary orofacial motor function. However, it is not known whether muscle pain causes direct or indirect changes in motoneuron excitability. In this study a monopolar needle stimulation technique was used to evoke the direct motor response (M-response) in the left masseter muscle and the heteronymous H-reflex in the left temporalis muscle as an indirect measure of motoneuron excitability. Series of 20 repeated electrical stimuli were delivered at 50% of maximal voluntary contraction (MVC) before, during, and after periods with experimental jaw-muscle pain in 11 healthy subjects. Pain was induced by standardized infusion of hypertonic (5%) saline into the mid-portion of the right masseter muscle. The mean pain intensity rating on a 100-mm visual analog scale was 42+/-5 mm. The short-latency responses (less than 6 ms) could be evoked in all subjects. Analysis of the latency and amplitude of the temporal H-reflex indicated no significant effect of jaw-muscle pain. The amplitude of the masseteric M-response was significantly smaller in the postpain condition than in the pain conditions (ANOVA, P=0.018), but no differences were found between the prepain and postpain conditions. In nine subjects, poststimulus periods (mean offset latency, 69.6+/-8.6 ms) with significantly (more than 50%) suppressed EMG activity were detected in the ipsilateral masseter muscle following the M-response (mean offset latency, 5.5+/-0.2 ms). These reflex responses did not show a systematic change during the pain conditions. In conclusion, acute contralateral jaw-muscle pain does not seem to modulate the motoneuron excitability as measured by the heteronymous H-reflex.

Adult↗

PubMed2002

Intrafusal fiber type composition of muscle spindles in the first human lumbrical muscle.

We studied muscle spindles in the first lumbrical muscle of adult humans using myofibrillar ATPase (mATPase) activity. We found that muscle spindles exhibited a marked variability with respect to the number, position, length and detailed histochemical features of nuclear bag1, nuclear bag2 and nuclear chain fibers. Regarding mATPase activity, the nuclear bag2 fibers displayed lower alkali-stable mATPase activity along their length and many nuclear bag1 fibers tended to have lower acid-stable activity in the outer B region, whereas nuclear chain fibers exhibited medium acid-stable mATPase activity at pH 4.6. Almost 10% of spindle fibers displayed atypical features, as they were either located only at one spindle pole or exhibited mixed characteristics at either pole. The number of intrafusal fibers per spindle varied between 8 and 24. Strikingly, only 2 pairs from 22 muscle spindles had identical allotments of their intrafusal fibers. Muscle spindles in the first human lumbrical muscle contained more intrafusal fibers (12.3 +/- 4 per spindle on average) and especially relatively more nuclear bag fibers compared to other human skeletal muscles. Since each spindle apparently represents a unique morphological and physiological entity, the observed variability in the number and characteristics of intrafusal fibers in the first human lumbrical muscle likely reflects a wide range of finely tuned muscle spindle responses.

Adenosine Triphosphatases↗

PubMed2005

Oestrogen receptor beta is present in both muscle fibres and endothelial cells within human skeletal muscle tissue.

Oestrogen receptor beta (ERbeta) is expressed in human skeletal muscle tissue. In the present study, we have developed an immunohistochemical method to reveal if ERbeta is located within the muscle fibres as well as within capillaries. Skeletal muscle biopsies were obtained from m. quadriceps femoris vastus lateralis in four healthy young subjects. Immunohistochemical triple staining was applied to transverse sections of paraffin-wax-embedded tissue. The basement membrane of muscle fibres and capillaries was identified by using an antibody to collagen IV, endothelial cells using an antibody to CD34 and ERbeta using a corresponding antibody. The ERbeta-positive (ERbeta+) nuclei were located within the muscle fibre defined by the localisation of collagen IV. ERbeta+ nuclei were also, for the first time, found in endothelial cells of capillaries in skeletal muscle tissue. Quantification was performed on transverse cryostat sections after performing a double staining (collagen IV and ERbeta). It was shown that 24% of the ERbeta+ nuclei were located within capillaries, and 76% were located within muscle fibres. In conclusion, ERbeta in human skeletal muscle tissue is expressed not only in the muscle fibres themselves, but also within the capillary endothelial cells. This observation might improve understanding of the physiological role of oestrogen and its receptor.

Adult↗

PubMed2000

Resident macrophages activated by lipopolysaccharide suppress muscle tension and initiate inflammatory response in the gastrointestinal muscle layer.

A great number of macrophages is found to be evenly distributed in the muscle layer of the gastrointestinal tract. We investigated their effects on smooth muscle contraction and the initiation of immune reactions such as inflammatory responses. Macrophages were demonstrated by the uptake of FITC-dextran and their ultrastructural features were elucidated by electron microscopy. Muscle layers of rats' ilea were incubated with lipopolysaccharide (LPS) for 4-8 h and the force of smooth muscle contraction was measured. The induction effect of inducible nitric oxide synthase (iNOS) on macrophages was then checked by immunohistochemistry. The expression of major histocompatibility complex (MHC) class II was also examined. Macrophages in the muscle layer were confirmed as resident macrophages and were different from a population of dendritic cells. After incubation with LPS, macrophages began to express iNOS and produced NO, and it reduced smooth muscle contraction. iNOS-immunopositive cells increased in a time-dependent manner. Macrophages also began to express MHC class II. The total number of macrophages did not alter after incubation. Results indicate that resident macrophages in the muscle layer induced iNOS as an inflammatory reaction, affected smooth muscle contraction, and initiated immune response in the smooth muscle layer of the gastrointestinal tract, when activated by LPS.

Animals↗

PubMed2001

Increased muscle glycogen content is associated with increased capacity to respond to T-system depolarisation in mechanically skinned skeletal muscle fibres from the rat.

The ability of mechanically skinned muscle fibres from the rat to respond to T-system depolarisation was studied in relation to muscle glycogen content. Muscle glycogen was altered by incubating extensor digitorum longus (EDL) muscles in Krebs solution without glucose or in Krebs solution with glucose (10 mM) and insulin (20 U.l-1). The glycogen content of muscles stored without glucose was rather stable between 30 and 480 min (11.27 +/- 0.39 mumol.g-1), while the muscles stored with glucose and insulin maintained an elevated and stable level of glycogen (23.48 +/- 1.67 mumol.g-1) between 100 and 360 min. Single mechanically skinned fibres from paired muscles, incubated in either glucose-free Krebs or in Krebs with glucose and insulin, were subjected to cycles of T-system depolarisation-repolarisation in a controlled environment (8 mM ATP, 10 mM creatine phosphate, 1 mM Mg2+, pH 7.10) and the force response was monitored until the force had declined to 50% of the maximum response (50% rundown). Fibres from muscles with a higher glycogen content reached 50% rundown after a larger number of depolarisations and displayed consistently larger average response capacity values, calculated as the sum of the force responses to 50% rundown divided by the maximum Ca(2+)-activated force response in that fibre. Thus skinned fibres originating from muscles with a higher glycogen content have an increased ability to respond to T-system depolarisation when the effect of metabolite accumulation is minimised and the function of glycogen acting as an energy source is by-passed. This provides direct support to the hypothesis that glycogen has a protective role in maintaining fibre excitability.

Adenosine Triphosphate↗

PubMed1993

Conformational adaptation of muscle: implications in cardiomyoplasty and skeletal muscle ventricles.

In dynamic cardiomyoplasty and other forms of muscle-powered cardiac assist, the stretch that should be applied to the skeletal muscle to obtain optimal resting tension remains unclear. To test the hypothesis that skeletal muscle is capable of conformational adaptation over time, the effect of altered resting tension on the chronic performance of a skeletal muscle ventricle was studied. In 7 mongrel dogs, skeletal muscle ventricles constructed from the lastissimus dorsi muscle were stimulated to contract for 12 weeks against an implantable mock circulation. The preload pressure was altered, thereby varying the resting tension of the latissimus dorsi. One group (group I; n = 5) was maintained at a preload of 80 mm Hg, whereas a second group (group II; n = 2) was maintained at 20 mm Hg. Adaptation to preload was observed. After 12 weeks, the pressure increase generated by the skeletal muscle ventricle at a preload of 20 mm Hg was only 35 +/- 2 mm Hg for group I compared with 44 +/- 5 mm Hg for group II. At a preload of 80 mm Hg, the pressure increase was 61 +/- 4 mm Hg for group I and only 34 +/- 6 mm Hg for group II. Adaptation of the latissimus dorsi to a new resting tension has important implications in the use of skeletal muscle for cardiac assist. Stretching the latissimus dorsi to its in situ length during cardiomyoplasty is not required for future muscle performance to be optimal.

Adaptation, Physiological↗

PubMed1987

Muscle-fibre architecture of the rat medial pterygoid muscle.

The detailed fibre architecture of the rat medial pterygoid muscle, including the courses and attachment points of muscle fibres, was investigated histologically in 10 micron thick serial sections in the horizontal, coronal and parasagittal planes. Four extramuscular tendinous sheets (external aponeuroses) and four intramuscular tendinous sheets (internal aponeuroses) were found. Three of the internal aponeuroses were arranged parallel to the rostro-caudal axis; the other was oblique to the rostro-caudal axis. Muscle fibres were located between internal aponeuroses, between external aponeuroses, between internal and external aponeuroses, between an internal aponeurosis and the periosteum, and between an external aponeurosis and the periosteum. The courses of muscle fibres were divided into three main groups: vertical, rostro-caudal and medio-lateral. Eight compartments were distinguished. The multiple movement of the medial pterygoid muscle seemed to be due to this compartmentalization. These findings suggested that the rat medial pterygoid muscle, like the rat masseter muscle, is mainly composed of multipennate muscles and compartmentalized into many muscle-fibre bundles running in different directions.

Animals↗

PubMed1994

Effects of the creatine analogue beta-guanidinopropionic acid on skeletal muscles of mice deficient in muscle creatine kinase.

To evaluate the effects of phosphocreatine (PCr) and creatine (Cr) depletion on skeletal muscles of mice deficient in muscle creatine kinase (M-CK), we have fed mutant mice a diet containing the creatine analogue beta-guanidinopropionic acid (beta GPA). After 8-10 weeks of feeding, accumulation of the creatine analogue in M-CK-deficient muscles was comparable to that observed in muscles of wild-type mice. Strikingly, and unlike wild types, mutants did not accumulate phosphorylated beta GPA, indicating that MM-CK is the only muscle CK isoform which can phosphorylate beta GPA. In M-CK-deficient muscles there was respective depletion of PCr, Cr and ATP levels to 31, 41 and 83% of normal. The average cross-sectional area of type 2B fibres in gastrocnemius muscles was very much reduced and was similar to type 1 and type 2A fibres which maintained their normal size. The maximal isometric twitch force developed by gastrocnemius-plantaris-soleus (GPS) muscle complexes of beta GPA-treated mutants was reduced by about 30%, but these muscles showed an increased fatigue resistance during 1 and 5 Hz contraction. Mitochondrial enzyme activities in the upper hind limb musculature of null mutants were 20-35% increased by the beta GPA diet. Altogether, these results provide evidence that certain functions of the creatine kinase/phosphocreatine (CK/PCr) system are not eliminated solely by the loss of M-CK.

Animals↗

PubMed1986

Development of an indirect flight muscle in a muscle-specific mutant of Drosophila melanogaster.

Stripe (sr) is a highly specific mutant affecting only one of the indirect flight muscles, the dorsal longitudinal muscle (DLM). In the homozygous condition the DLM is reduced in size. In the hemizygous condition (sr/Df(3)sr) no DLM is present in the adult, though all other thoracic muscles are present. In the early stages of pupation, DLM development in sr/Df(3)sr is no different from that in wild type. Adult myocytes collect around target larval muscles and fuse to form myotubes; myofilaments are synthesized. Subsequently (35-hr pupa) the DLM commences to degenerate, forming random clumps of vacuolated muscle tissue. Adjacent muscles are unaffected and develop normally. In the adult a neuroma-like mass of nerve tissue is maintained where the DLM would normally be located. In this mass many abnormal synapses (hemisynapses) are seen: presynaptic specializations occur in the absence of any postsynaptic structure. Small remnants (less than 16-microns diameter) of muscle tissue are sometimes found in the neuroma-like mass. Such remnants resemble slow muscle, not the normal fast type of DLM. These data suggest a possible muscle origin from primary and secondary myotubes. The DLM motor axons are present in the neuroma-like mass, persisting even with the virtual degeneration of their end target. Thus, motoneurons and presynaptic specializations can survive independently of postsynaptic targets.

Animals↗

PubMed1996

Structural basis for oxygen delivery: muscle capillaries and manifolds in tuna red muscle.

We summarize our morphometric data on fiber vascularization and aerobic capacity in red muscle of tuna (Katsuwonus pelamis), compared to intensely aerobic flight muscles of hummingbird (Selasphorus rufus, BW 3-4 g) and bat (Eptesius fuscus, BW 15-16 g, Pipistrellus hesperus, BW 3-5 g). Three characteristic features of high flux paths for oxygen: (a) small fiber size, (b) dense capillary network and (c) high mitochondrial volume density were found in tuna, but they were not as pronounced as in hummingbird and bat flight muscles. A particular arrangement of capillary manifolds, also seen in flight muscle of birds but not in bats, was found in tuna, forming dense envelopes of capillary branches around portions of muscle fibers. However, all indexes of fiber capillarization were relatively low in tuna red muscle for its mitochondrial volume, compared with other intensely aerobic muscles. Capillary length per unit volume of mitochondria, and capillary surface per mitochondrial inner (and outer) membrane surface area, were about one half of those in hummingbird or bat flight muscles. Consistent differences exist in the size of the capillary network for the size of the mitochondrial compartment in highly aerobic red muscle of tuna compared with bird and mammal.

Aerobiosis↗

PubMed2006

Classification of muscle spindle afferents innervating the masseter muscle in rats.

Taylor et al. [Taylor, A., Durbaba, R., Rodgers, J.F., 1992a. The classification of afferents from muscle spindles of the jaw-closing muscles of the cat. J Physiol 456, 609-628] developed a method to classify muscle spindle afferents using succinylcholine (Sch) and ramp and hold stretches. They demonstrated that cat jaw muscle spindle afferents show high proportion of intermediate responses to ramp and hold jaw stretch. Together with observations on the responses to Sch their data suggests that the majority of jaw muscle spindle afferents are influenced by a combination of nuclear bag(2) and nuclear chain fibres. Relatively few are influenced solely by nuclear bag(1) fibres. The purpose of this study was to categorize jaw muscle spindle afferent in rodents in response to ramp and hold stretches. Several measures were used to classify spindle afferents including (1) conduction velocity, (2) coefficient of variation (C.V.) of the interspike interval during jaw opening, and (3) the dynamic sensitivity and the initial discharge of spindle afferents before and after succinylcholine infusion (Sch, 100mg/kg, i.v.). Consistent with observations in the cat jaw muscles, the distribution of the conduction velocity and the C.V. of Vmes masseter afferents were unimodal. Therefore, these parameters were of little value in functional classification of spindle innervation. Succinylcholine injection either markedly increased the dynamic sensitivity or produced no change in Vmes afferents. Unlike cat jaw muscle spindle afferents, the effect of Sch on the initial discharge was not clearly separable from those responding or not responding to Sch. These results suggest that rat jaw muscle spindle afferents, have physiological properties that are primarily intermediate in nature and are likely to reflect a predominance of influence from nuclear bag(2) and chain fibres. However, the distinction between bag(2) and chain fibres influences is not as clearly defined in the rat compared to the cat.

Action Potentials↗

PubMed2006

Inspiratory muscle training in patients with heart failure and inspiratory muscle weakness: a randomized trial.

OBJECTIVES: This study sought to evaluate the effects of inspiratory muscle training in inspiratory muscle strength, as well as in functional capacity, ventilatory responses to exercise, recovery oxygen uptake kinetics, and quality of life in patients with chronic heart failure (CHF) and inspiratory muscle weakness. BACKGROUND: Patients with CHF may have reduced strength and endurance in inspiratory muscles, which may contribute to exercise intolerance and is associated with a poor prognosis. METHODS: Thirty-two patients with CHF and weakness of inspiratory muscles (maximal inspiratory pressure [Pi(max)] <70% of predicted) were randomly assigned to a 12-week program of inspiratory muscle training (IMT, 16 patients) or to a placebo-inspiratory muscle training (P-IMT, 16 patients). The following measures were obtained before and after the program: Pi(max) at rest and 10 min after maximal exercise; peak oxygen uptake, circulatory power, ventilatory oscillations, and oxygen kinetics during early recovery (VO2/t-slope); 6-min walk test; and quality of life scores. RESULTS: The IMT resulted in a 115% increment Pi(max), 17% increase in peak oxygen uptake, and 19% increase in the 6-min walk distance. Likewise, circulatory power increased and ventilatory oscillations were reduced. The VO2/t-slope was improved during the recovery period, and quality of life scores improved. CONCLUSIONS: In patients with CHF and inspiratory muscle weakness, IMT results in marked improvement in inspiratory muscle strength, as well as improvement in functional capacity, ventilatory response to exercise, recovery oxygen uptake kinetics, and quality of life.

Breathing Exercises↗

PubMed2026

C9orf72-associated poly-GR in skeletal muscle leads to neuromuscular junction deficits and muscle atrophy.

Hexanucleotide repeat expansions in C9orf72 produce dipeptide repeat (DPR) proteins that are widely expressed, including in the nervous system and skeletal muscle. Among these DPRs, arginine-containing proteins, poly-GR and poly-PR, are toxic in the nervous system, but whether DPRs in skeletal muscle contribute to amyotrophic lateral sclerosis (ALS) pathogenesis is unclear. Here, we show that muscle-restricted expression of poly-GR drives motor deficits in mice, including muscle atrophy and neuromuscular junction (NMJ) deficits. Poly-GR in muscle interacted with the NMJ key organizer MuSK and promoted MuSK degradation, disrupting postsynaptic structure and impairing neuromuscular transmission. Importantly, a MuSK agonist antibody (X-17) stabilized NMJs and rescued neuromuscular transmission. Moreover, poly-GR in muscle activated the integrated stress response (ISR), elevating eIF2α phosphorylation and broadly suppressing protein translation. ISR inhibition with ISRIB restored translation and MuSK protein levels and ameliorated both muscle atrophy and NMJ deficits. These findings demonstrate that skeletal muscle actively contributes to C9orf72-ALS pathology. Targeting muscle with ISRIB offers a therapeutic strategy to preserve motor function in C9orf72-ALS.

Animals↗

PubMed2000

Expression of human IAP-like protein in skeletal muscle: a possible explanation for the rare incidence of muscle fiber apoptosis in T-cell mediated inflammatory myopathies.

In Polymyositis (PM) and sporadic Inclusion Body Myositis (s-IBM), the CD8(+) cytotoxic T cells invade the muscle membrane and release perforin and granzyme B to induce cell death. Although granzyme B is a direct activator of executioner caspases, there is no convincing evidence of apoptosis in the muscle fibers of these patients. To search for an explanation, we examined the muscle expression of the human IAP-Like Protein (hILP), an evolutionarily conserved cell death suppressor, that exerts major anti-apoptotic effects by inhibiting the executioner caspases. Muscle biopsy specimens from patients with inflammatory myopathies and controls were studied with: (a) immunocytochemistry using antibodies against hILP and caspase-3 in single and double-labeled confocal laser microscopy; (b) immunoblotting of muscle extracts immunoreacted with anti-hILP antibodies; and (c) subcellular fractionation of muscle lysates immunoreacted with antibodies against hILP. We found that hILP is expressed on the sarcolemmal region and co-localizes with dystrophin. Caspase-3 is undetectable. Subcellular fractionation of the muscle specimens confirmed that hILP is a membrane-associated protein. By immunoblotting, the 57 kD hILP was abundantly expressed in the normal as well as the diseased muscles. We conclude that in s-IBM and PM the expression of hILP, a major cell death suppressor, on the muscle membrane may prevent the induction of apoptosis by the autoinvasive cytotoxic T cells on the cell surface, by inhibiting the caspase activation.

Apoptosis↗