Ultrastructural characteristics and DNA immunocytochemistry in human immunodeficiency virus and zidovudine-associated myopathies

Electron microscopic features of muscle biopsies from 13 human immunodeficiency (HIV)-positive patients who had myopathy while receiving zidovudine (AZT) were compared with biopsies from five patients with HIV-induced myopathy who were not treated with AZT. All specimens showed disorganization of the myofibrillar structures, along with a varying degree of nemaline (rod) bodies, vacuolization, inflammation, and endothelial tubuloreticular profiles. One untreated and all AZT-treated patients had cytoplasmic bodies, which in the latter were abundant, large, and irregular. Two untreated patients had a peculiar osmiophilic destruction of the muscle fibers, with numerous tubuloreticular profiles in the endothelial cells and brisk inflammation that included lymphoplasmatoid cells. The AZT-treated group had ubiquitous abnormal mitochondria that complemented the presence of ragged red fibers seen by light microscopy. There was subsarcolemmal proliferation of mitochondria, with marked variation in size and shape and proliferation or disorganization of their cristae. Paracrystalline inclusions were seen in one patient. Blind re-examination of the electron micrographs showed abnormal mitochondria that readily distinguished patients with AZT-associated myopathy from those with untreated HIV-induced myopathy. Immunocytochemistry using antibodies to single- and double-stranded DNA revealed severe reduction of mitochondrial DNA compared with the normal nuclear DNA. Although the myopathies associated with HIV and AZT share common myopathologic features, the mitochondrial abnormalities are unique to the AZT-treated patients. Since mitochondrial DNA is specifically reduced, the structural changes noted on electron microscopy are probably associated with mitochondrial dysfunction. Zidovudine, a DNA chain terminator that inhibits the mitochondrial gamma-DNA polymerase, is toxic to muscle mitochondria.     

Myopathic changes in indirectly stimulated mouse diaphragm after ecothiopate in vitro.

Mouse phrenic nerve-hemidiaphragms were stimulated in vitro in the presence of the anticholinesterase ecothiopate iodide and prepared for light and electron microscopy at different times during and after the appearance of prolonged contractions localized at the endplate. The earliest changes were at the subsynapse, without damage to the plasma membrane, and comprised hypercontraction of the sarcomeres, dilatation and vesiculation of the sarcoplasmic reticulum and the mitochondria, and dissolution of the Z-lines. Later there was damage to the plasma membrane. Also appearing later in the junctional region, but separated from the subsynapse by apparently normal muscle, were extrasynaptic hypercontractions, with a plasma membrane initially undamaged, but which became permeable after the contractile material divided into contraction clots. A hypothesis is proposed for the formation of such hypercontractions by abnormal mechanical factors arising from different contractile states along the length of the fibre, and is discussed with the role of prolonged transmitter action in the aetiology of myopathy.     

Porin-type1 proteins in sarcoplasmic reticulum and plasmalemma of striated muscle fibres

Summary The location of porin-type1 proteins in mammalian striated muscle has been assessed using immunogold electron microscopy with an anti-porin 31HL monoclonal antibody as the primary antibody. Gold particles were found on the mitochondrial outer membrane, the sarcoplasmic reticulum and plasmalemma in longitudinal sections of rat and rabbit skeletal muscle and rabbit and sheep cardiac muscle. The relative densities of gold particles in the mitochondrial outer membrane, sarcoplasmic reticulum and plasmalemma were 7:3:1 in white sternomastoid muscle, for example. Skeletal and cardiac sarcoplasmic reticulum vesicles, which had been fractionated by discontinuous sucrose density centrifugation, were subjected to SDS-polyacrylamide gel electrophoresis and Western blotting. The anti-porin 31HL monoclonal antibody detected a band of relative molecular mass (M_r) 31 000 in all muscle sarcoplasmic reticulum vesicle fractions and also in liver mitochondria. The intensity of immunostaining of the sarcoplasmic reticulum fractions was 2.5–10% that of mitochondrial outer membranes per g of membrane protein blotted. Contamination of the sacroplasmic reticulum fractions by mitochondrial outer membrane was <0.75% as determined from the specific activity of monoamine oxidase. Thus, only a small part of the porin detected in sarcoplasmic reticulum vesicles can be attributed to mitochondrial contamination. These results show that porin-type1 immunoreactivity is not restricted to mitochondria but found in the sarcoplasmic reticulum and plasmalemma of both mammalian skeletal and cardiac muscle.     

Possible role of cytoskeleton in intracellular arrangement and regulation of mitochondria

The origin of significant differences between the apparent affinities of heart mitochondrial respiration for exogenous ADP in isolated mitochondria in vitro and in permeabilized cardiomyocytes or skinned fibres in situ is critically analysed. All experimental data demonstrate the importance of structural factors of intracellular arrangement of mitochondria into functional complexes with myofibrils and sarcoplasmic reticulum in oxidative muscle cells and the control of outer mitochondrial membrane permeability. It has been shown that the high apparent K(m) for exogenous ADP (250-350 mM) in permeabilized cells and in ghost cells (without myosin) and fibres (diameter 15-20 mm) is independent of intrinsic MgATPase activity. However, the K(m) may be decreased significantly by a selective proteolytic treatment, which also destroys the regular arrangement of mitochondria between sarcomeres and increases the accessibility of endogenous ADP to the exogenous pyruvate kinase-phosphoenolpyruvate system. The confocal microscopy was used to study the changes in intracellular distribution of mitochondria and localization of cytoskeletal proteins, such as desmin, tubulin and plectin in permeabilized cardiac cells during short proteolytic treatment. The results show the rapid collapse of microtubular and plectin networks but not of desmin localization under these conditions. These results point to the participation of cytoskeletal proteins in the intracellular organization and control of mitochondrial function in the cells in vivo, where mitochondria are incorporated into functional complexes with sarcomeres and sarcoplasmic reticulum.     

Pathogenesis of skeletal muscle necrosis induced by tarantula venom

The pathogenesis of myonecrosis induced by venoms of the Arkansas tarantula (Dugesiella hentzi, Girard) and the Honduran tarantula (Aphonopelma spp.) was studied using light and electron microscopy, scanning electron microscopy and x-ray microprobe analysis, and histochemistry. White mice were injected intraperitoneally with a sublethal dose of tarantula venom. Gross examination 24 hr after injection revealed white areas of apparent calcification in the diaphragm muscle. Light microscopic examination at 15 min revealed hypercontracted muscle cells, and necrotic masses containing areas of condensed myofibrils and clumps of mitochondria. By 12 hr numerous phagocytic cells were present around degenerated muscle cells. Electron microscopic examination revealed a myonecrosis of rapid onset with plasma membrane rupture and contraction bands 15 min after injection. At 3 hr only small patches of plasma membrane remained and mitochondrial changes such as swelling, dense intracristal spaces, partitioning, and flocculent densities were prominent. By 12 and 24 hr very dark spicular densities were present in mitochondria and numerous phagocytic cells were located within the intact basal lamina of necrotic cells. X-ray analysis and histochemistry of 24 hr samples showed that necrotic cells contained very high levels of calcium and phosphate. These two tarantula venoms caused a rapid onset myonecrosis in which the primary injury was rupture of the plasma membrane followed by inability of mitochondria and sarcoplasmic reticulum to maintain normal levels of calcium in the cytoplasm leading to cell death.     

Myocardial ultrastructure and electrocardiograms of the hummingbird under normal and experimental conditions

Ventricular myocardium from several adult specimens of hummingbirds (Eupetomena macroura macroura) were subjected to study by electrocardiography and by light and electron microscopy under normal and experimental conditions as provided by injection of 2,4-dinitrophenol (DNP) and ether anesthesia. The birds were captured in Brazil, and were studied because of their high heart rates 428/460 minute on the average, seeking correlations of structure and function under normal conditions as well as after pharmacological stimuli. Under normal conditions, the hummingbird showed a highly developed sarcoplasmic reticulum, many gigantic mitochondrial with numerous tightly packed parallel mitochondrial cristae and tubules, and few small, dark bodies. The amount of sarcosomes is approximately equivalent to that of myofibrils. As seen in longitudinal sections of muscle fibers, often the junctions between successive mitochondria and both indentations of mitochondria and of the nuclear envelope occurred at the level of the Z bands. This gave the impression that contraction of the myofibrils shortened the nucleus and caused it to wrinkle. Most mitochondrial bulged at their middle as if they had been compressed between successive Z bands, suggesting a more resistant area at the level of these bands than in the rest of the myofibril. Almost no glycogen granules were found, probably because the high metabolic rate of the heart did not allow free storage of such carbohydrates. The administration of DNP was responsible for changes in the ECG (tachycardia and other alterations) and in the structure of the myocardium: large dilations in the sarcoplasmic reticulum and the appearance of small spaces in the mitochondria.     

Muscle damage produced by chronic alcohol consumption.

The effects of chronic alcohol consumption on skeletal muscle, independent of nutritional factors, were studied. Chronic alcohol ingestion led to striking ultrastructural changes in skeletal muscle, including intracellular edema, enlarged and distorted mitochondria, dilatation of sarcoplasmic reticulum, and increased amounts of fat and glycogen. Actomyosin was isolated from skeletal muscle of baboons and volunteers fed alcohol. In this preparation, ATPase activity and the calcium sensitivity of ATPase were decreased. The isolated actomyosin displayed reduced contractility in vitro, measured by the association of actin and myosin and the response to adenosine diphosphate (ADP). In 2 of 3 volunteers, isolated membranes of the sarcoplasmic reticulum exhibited decreased calcium uptake. The pressure-rate product was increased in some of the volunteers after submaximal or maximal work. The changes decribed in this study were found after alcohol administration had been discontinued, and they may play a role in the development of alcoholic myopathy and cardiomyopathy.     

Myopathy,lactic acidosis,and sideroblastic anemia: A new syndrome

We describe 2 sibs (brother and sister) with myopathy, sideroblastic anemia, lactic acidosis, mental retardation, microcephaly, high palate, high philtrum, distichiasis, and micrognathia. Very low levels of cytochromes a, b, and c were detected in the patients' muscle mitochondria. Deposition of iron within the mitochondria of bone marrow erythroblasts was observed on electron microscopy. Irregular and enlarged mitochondria with paracrystalline inclusions were also seen on electron microscopy of the patients' muscle specimen. Examination of DNA from the affected sibs showed no deletions in the mitochondrial DNA nor the mutations identified in the syndromes of mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) or myoclonus, and epilepsy associated with rugged-red fibers (MERRF). Since the parents were first cousins and 2 of 6 sibs (male and female) were affected, we suggest that the syndrome expressed by our patients represents a previously unknown autosomal recessive disorder that includes mitochondrial myopathy, lactic acidosis, and sideroblastic anemia. © 1995 Wiley-Liss, Inc.     

Neuropathy Associated with Mitochondrial Disorders

Altered mitochondria within peripheral nerves were found in most cases of mitochondrial myopathy, in all cases of hereditary motor and sensory neuropathy with optic atrophy (HMSIM VI) and in 25 cases out of a larger series of 280 unselected neuropathies studied by electron microscopy for diagnostic purposes. The mitochondrial changes differed from those seen in the corresponding skeletal muscle fibres. They comprised enlargements with an amorphous matrix and distorted cristae, hexagonal para-crystalline inclusions, sometimes longitudinally arranged in a zig-zag pattern, prominent cristae containing oblique striations and a variety of rare changes. Most mitochondrial abnormalities were found in Schwann cells. An occasional perineurial cell was also involved showing a unique paracrys-talline inclusion. An increase of the number of mitochondria was noted in smooth muscle and endothelial cells of epineurial arterioles in three cases of mitochondrial encephalomyopathy (two cases with Kearns Sayre syndrome, and one with mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes, i.e., "MELAS"). Neuropathy was present in all cases of mitochondrial myopathy as judged by morphometric analysis. Whether neuropathy is caused directly by mitochondrial dysfunction or by other pathogenetic mechanisms remains to be determined. Yet peripheral motor and sensory neurons with their peripheral axons are postmitotic, terminally differentiated cells which should be similarly prone to deleterious deletions of mitochondrial DNA as has been suggested as an etiologic factor for the predilection of mitochondrial diseases in muscle and brain.     

Beta-amyloid protein-containing inclusions in skeletal muscle of apolipoprotein-E-deficient mice.

The tibialis anterior muscle and soleus muscle of apolipoprotein-E-deficient mice were examined by light and electron microscopy. By light microscopy, sarcoplasmic inclusions were seen in tibialis anterior muscle and 40% of type 2 myofibers were affected in all animals over 8 months of age. These inclusions reacted for nonspecific esterase, cytochrome oxidase, and myoadenylate deaminase and were also periodic acid Schiff positive and stained basophilic with hematoxylin. Moreover, they reacted immunocytochemically with an antibody specific to fragment 17 to 24 of the published sequence of Alzheimer's cerebrovascular amyloid peptide. Immunoreactivity was lost when the antibody was adsorbed with the appropriate synthetic peptide. Ultrastructurally, the inclusions consisted of tubular arrays and were similar to those observed in human muscle in several pathological conditions. In type 1 myofibers of both tibialis anterior and soleus muscle, however, mitochondrial abnormalities including an increase in their number and size were detected, but tubular aggregates were not seen. These large mitochondria possessed an electron-dense inner chamber with an increased number of tightly packed cristae. The results obtained suggest that in these mice there is a disturbed lipid metabolism in skeletal muscle fibers that manifests itself with an accumulation of phospholipid in the form of sarcoplasmic reticulum tubules in the type 2 fibers and enlarged mitochondria with tightly packed cristae in the type 1 fibers. In addition, beta-amyloid protein was closely associated with the accumulated tubules and vesicles of sarcoplasmic reticulum and may represent dysregulation of amyloid precursor protein metabolism.     

Myopathic alterations in extraocular muscle of rats subchronically fed pyridostigmine bromide

To determine if alterations in extraocular muscle morphology occur after subchronic oral administration of pyridostigmine bromide, rats were continuously fed 90 mg/kg in meal and examined at 1, 2, 4, 7, and 15 days. Within the first day, blood acetylcholinesterase activity was reduced by 87% and remained inhibited by 74-91% during the study. Light microscopy demonstrated that by day 1 approximately 3% of the extraocular myofibers were shrunken and invaded by inflammatory cells. The most severe degenerative changes consisting of vacuoles and inflammatory cell infiltration occurred at day 1 with progressively less severe changes at days 2 and 4. At days 7 and 15, 1.3-4.5% of the myofibers still exhibited damage. Ultrastructurally, all presynaptic areas were normal but the postsynaptic areas of affected myofibers at days 1, 2, and 4 showed myofilament and Z-band dissolution, mitochondrial inclusions, subneural fold and T-tubule/sarcoplasmic reticulum vacuolization and subneural fold depth reduction. By days 7 and 15, these changes were diminished in some cases and in others alterations appeared similar to day 1. We conclude that subchronic feeding of pyridostigmine bromide induces myopathic rather than neurogenic changes in rat extraocular muscle and that the myopathy is different in these muscles than in the diaphragm from the the same rats.     

Ultrastructure of cardiac muscle from dystrophic mice

The ultrastructure of cardiac muscle from dystrophic mice was compared with that of their non-dystrophic littermates. Among the abnormalities observed in the fine structure of the muscle fibers in the dystrophic animals were increased lipid, swollen mitochondria, swollen tubules of the sarcoplasmic reticulum, supercontracted myofibrils, and partially separated intercalated discs. The ventricular muscle appeared to be the region most often affected; in only one of eleven animals did the atrium show discernible effects of the dystrophy. Although a progression of degenerative events seemed to occur, a time schedule could not be determined because of the large variation among hearts of dystrophic animals. The ultrastructure of the hearts from non-dystrophic littermates was normal. It appears that the depressed cardiac function caused by the myopathy may play a major role in the early death of the dystrophic mice, as in the case of dystrophic hamsters and men. Most of the ultrastructural abnormalities observed could be accounted for if there were an elevation of intracellular free Ca⁺⁺ concentration.     

Nature of muscular change in osteomalacia: light- and electron-microscope observations.

Thirteen muscle biopsy specimens (mainly the gluteus maximus) from 12 patients with laboratory confirmation of osteomalacia and proximal muscle weakness in 10 were examined by light and electron microscopy. Light microscopy revealed mild diffuse non-specific atrophy of the muscle fibres in 10 cases, severe generalised atrophy in one and patchy group atrophy in one. There was no myopathic change in specimens from cases with either a nutritional aetiology, or a mixed aetiology. The former, mostly women gave a history of severe chronic malnutrition often accompanied by repeated pregnancies and prolonged lactation; those with a mixed aetiology gave, in addition, evidence of a metabolic or endocrine disorder such as hyperparathyroidism, hyperthyroidism, uraemia, or treatment with anti-epileptic drugs or were of uncertain origin. Electron-microscope examination of muscle from the nutritional group showed atrophic changes in the fibres, such as loss of myofibrils, prominence of mitochondria and glycogen, loosening and folding of the basement-membrane but good preservation of the remaining myofibrils. In contrast muscle from cases of mixed aetiology showed, in addition to the atrophic features, clear degenerative changes in the myofibrils and the mitochondria, accumulation of amorphous material at the site of myofibrillar loss and of lipofuscin in muscle fibres, vascular endothelium and satellite cells. The earliest degenerative change was in the "I" band, involving actin filaments and "Z" line. The triads were generally preserved but the sarcoplasmic reticulum appeared affected in a patient with tetany and severe mitochondrial degeneration. In a patient with thyrotoxicosis, proliferation of central nuclei, "Z" line streaming and formation of "T" tubular aggregates were seen. In one patient with hyperparathyroidism and hypercalcaemia, severe myofibrillar degeneration and mitochondria showing osmiophilic deposits, possibly of calcium phosphate, were encountered. It is concluded: (1) that all osteomalacic muscle weakness is not myopathic but a non-specific atrophy occurring probably on the basis of disuse and malnutrition, and (2) patients with an added metabolic or endocrinological disorder show in addition to the atrophy, degenerative changes in the muscle fibre and its sub-cellular components consistent with myopathy, and these patients should be clearly distinguished from those with a background of malnutrition only.     

Early ultrastructural changes in skeletal muscle exposed to the local anaesthetic bupivacaine (Marcaine).

The local anaesthetic drug bupivacaine is known to produce a degeneration in mammalian muscle fibres which is followed by regeneration. In an attempt to define the site of action of this drug and the cell type responsible for the subsequent fibre regeneration, first lumbircal muscles of rats were exposed in vitro to concentrations of 10(-2), 5 X 10(-3), and 10(-3)M bupivacaine for periods ranging from 5 min to 3 h. An electron microscopic study of muscles exposed to 10(-2) and 5 X 10(-3)M bupivacaine revealed an initial supercontraction followed by evidence of severe and probably irreversible injury to plasma membrane, sarcoplasmic reticulum and mitochondria. Myonuclei showed signs of injury early, but satellite cells were found relatively resistant. The basal lamina remained intact throughout and myelinated axons did not suffer damage. However, both endothelial cells of capillaries and fibrocytes showed degenerative changes. Muscles exposed to 10(-3)M bupivacaine showed little change after incubation for 3 h. It is concluded that increased intracellular levels of Ca++ ions may play a part in the pathogenesis of muscle injury induced by bupivacaine and that their source may be the sarcoplasmic reticulum. The role of the satellite cell in the regeneration that follows this injury was not clearly established.     

Ultrastructure of the aging myocardium: A morphometric approach

Left ventricular tissue from adult and aging Syrian hamster heart was compared at the ultrastructural level, using both qualitative and morphometric electron microscopy. The aging myocardium often showed indented nuclei, lipid droplets and aggregations of dense bodies. The volume fractions of muscle cells occupied by mitochondria, lipid and lysosomes (including both primary lysosomes and residual bodies) was significantly greater in the old animals, while there was no significant difference in nuclear volume fraction or myofibrillar mass. Sarcoplasmic reticular volume and membrane surface area fell during aging. The area of mitochondrial inner membrane plus cristae per mitochondrial volume also fell. When sarcoplasmic reticular and mitochondrial area were expressed per myofibrillar volume fraction, the sarcoplasmic reticular ratio fell, while the mitochondrial parameter remained constant. Discoordinate aging of cellular components in the mammalian myocardium is proposed.     

Distribution of COX-negative mitochondria in myofibers of rats intoxicated with Senna occidentalis seeds

We have described that administration of seeds or parts of the seed of Senna occidentalis (coffee senna) for long periods, induces histochemical changes in the skeletal muscles of hens and rats that are characteristic of a mitochondrial myopathy--as decrease of SDH and COX activity, with some COX negative fibers. In this experimental model of mitochondrial myopathy, as in many human mitochondrial diseases, there is a random distribution of COX negative fibers. Some fibers are completely COX negative while others are partially negative and others are completely positive. In the present work we have studied the distribution of COX negative mitochondria at transmission electron microscopy in skeletal muscle of rats in this experimental myopathy. In myofibers of intoxicated animals the expression of COX was heterogeneous. The histochemical reaction was observed in the internal membrane (more evident in mitochondrial cristae) of all mitochondria of some myofibers, while it was almost absent in other myofibers. In these myofibers the great part of the mitochondria were negative for COX reaction while other ones had a weak expression of this enzyme (dot or focal expression of COX). Our results indicated that the COX mitochondrial activity is heterogeneously impaired in myofibers of rats intoxicated with S. occidentalis. These abnormalities remember those observed in some types of human mitochondrial myopathies.     

Ultra-high resolution scanning electron microscopic studies on the sarcoplasmic reticulum and mitochondria in the rat cardiac and skeletal muscle fibers

The three-dimensional structure of the sarcoplasmic reticulum (SR), transverse (T)-axial tubular system and mitochondria in cardiac and skeletal muscle fibers of the rat was examined by ultra-high resolution scanning electron microscopy after removal of the cytoplasmic matrices and myofilaments by the aldehyde-osmium-dimethyl sulfoxide-osmium procedure^1,2. Between the cardiac and the skeletal muscle fibers, striking differences in the three-dimensional structure of the mitochondria and of the SR were observed.     

Mitochondrial diseases and myopathies: a series of muscle biopsy specimens with ultrastructural changes in the mitochondria.

From 1986 to 1991, 472 muscle biopsy specimens from patients from different hospitals in Norway were examined. Of these, 364 were embedded for electron microscopy, and 194 were examined with electron microscopy. Ultrastructural alterations in the mitochondria were detected in 49 of these specimens. Characteristic electron microscopic findings included subsarcolemmal accumulation of abnormal mitochondria of various shapes and sizes, often containing electron-dense granules and sometimes lipid vacuoles in the mitochondria and diffusely electron-lucent matrix space. Paracrystalline inclusion bodies were seldom seen in specimens from young patients, but in some cases mitochondrial electron-dense granules at the cristae were found. These amorphous densities are consistent with lipoproteins, suggesting that they may represent an early stage of paracrystalline inclusions. Biochemical and genetic exploration of the patients with biopsy specimens suggesting mitochondrial disease indicated maternally genetic inheritance and an enzyme defect in the respiratory chain in 21 patients in two families. Three patients had MELAS syndrome, 7 Marinesco-Sj?gren syndrome, and 2 Kearns-Sayre syndrome. Five family members had ptosis, cardiomyopathy, mild myopathy, and increased lactate in cerebrospinal fluid and serum. In addition to the diseases mentioned above, changes in the mitochondria were detected in other conditions such as Rett's syndrome (n = 1), ornithine transcarbamylase deficiency (n = 2), and hypothyroidism (n = 2) as well as in 3 patients with clinical and laboratory results indicative of inflammatory myopathy and 3 patients with clinical and laboratory findings consistent with peripheral neuropathy. It is concluded that, although ultrastructural changes in the mitochondria may represent unspecific findings, electron microscopic examination of muscle biopsy specimens is a useful screening method to select specimens for further biochemical analysis and to obtain an early and more precise diagnosis of the disease.     

The effects of bilateral adrenalectomy on the fine structure of the rat myocardium

The subcellular effects of bilateral adrenalectomy on the rat myocardium were examined on 50 male rats. The animals, divided into groups of ten, were killed 3, 17, 18, 19 and 21 after adrenalectomy. The early changes consisted of moderate intracellular edema of many cardiac muscle cells and disarrangement of their myofibrils. The late changes consisted of prominent intracellular edema of many cardiac muscle cells, destruction of numerous myofibrils, dilatation of the sarcoplasmic reticulum and accumulation of numerous irregular mitochondria in subsarcolemma areas of the sarcoplasm. The lipofuscin granules seemed to be increased in number. Many endothelial cells were edematous and platelet aggregations filled the lumen of some small vessels.     

Ultrastructural features of the muscle fibers in congenital hypothyroidism

Summary Muscles of three patients (2 years, 2 years and 7 months, and 11 years of age) affected by congenital hypothyroidism due to dysgenesis of the thyroid gland were studied by electron microscope. The biopsies were performed on the quadriceps muscle. Several alterations were found in the ultrastructure of the muscle fibers. The contractile material underwent atrophy by two recessive processes: by reduction and by degeneration. The former, which affected mainly the white fibers, led to the progressive detachment of myofilaments from the periphery of the myofibrils while they maintainad a normal arrangement in the center. Consequently, their diameter decreased and their interfibrillar spaces enlarged. The latter enlargment, involving the red fibers, caused areas of dedifferentiation involving either the contractile apparatus or the other cell organelles. Modifications of the sarcolemma and basement membrane were seen in the fibers affected by the atrophying processes of the contractile material. Changes of the ultrastructure of the sarcoplasmic reticulum and of the T system were observed with numerous morphological abnormalities of the mitochondria. In addition, accumulation of glycogen and striking changes of the satellite cells were found. The ultrastructural findings are reviewed and discussed in relation to the literature on hypothyroid myopathy.