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Abstract Myopathies are common manifestations of mitochondrial diseases. To investigate whether gene replacement can be used as an effective strategy to treat or cure mitochondrial myopathies, we have generated a complex I conditional knockout mouse model lacking NDUFS3 subunit in skeletal muscle. NDUFS3 protein levels were undetectable in muscle of 15‐day‐old smKO mice, and myopathy symptoms could be detected by 2 months of age, worsening over time. rAAV9‐Ndufs3 delivered systemically into 15‐ to 18‐day‐old mice effectively restored NDUFS3 levels in skeletal muscle, precluding the development of the myopathy. To test the ability of rAAV9‐mediated gene replacement to revert muscle function after disease onset, we also treated post‐symptomatic, 2‐month‐old mice. The injected mice showed a remarkable improvement of the mitochondrial myopathy and biochemical parameters, which remained for the duration of the study. Our results showed that muscle pathology could be reversed after restoring complex I, which was absent for more than 2 months. These findings have far‐reaching implications for the ability of muscle to tolerate a mitochondrial defect and for the treatment of mitochondrial myopathies.

Patients with autoimmune myositis typically present with muscle weakness, elevated serum levels of muscle enzymes, and abnormal muscle biopsies. However, patients with other acquired myopathies or genetic muscle diseases may have remarkably similar presentations. Making the correct diagnosis of another muscle disease can prevent these patients from being exposed to the risks of immunosuppressive medications, which benefit those with myositis, but not those with other types of muscle disease. Here, we review some of the most common acquired and inherited muscle diseases that can mimic autoimmune myositis, including inclusion body myositis, limb girdle muscular dystrophies, metabolic myopathies, mitochondrial myopathies, and endocrine myopathies. We emphasize aspects of the medical history, physical exam, laboratory evaluation, and muscle biopsy analysis that can help clinicians distinguish myositis mimics from true autoimmune myositis. [ABSTRACT FROM AUTHOR]

One large group of hereditary myopathies characterized by recurrent myoglobinuria, almost invariably triggered by exercise, comprises metabolic disorders of two main fuels, glycogen and long-chain fatty acids, or mitochondrial diseases of the respiratory chain. Differential diagnosis is required to distinguish the three conditions, although all cause a crisis of muscle energy. Muscle biopsy may be useful when performed well after the episode of rhabdomyolysis. Molecular genetics is increasingly the diagnostic test of choice to discover the underlying genetic basis. [ABSTRACT FROM AUTHOR]

The toxic myopathies are a clinically and pathologically diverse group of disorders that can be caused by a variety of therapeutic agents used in clinical practice, as well as various venoms and other biological toxins. The most important iatrogenic causes are the statin and fibrate cholesterol-lowering agents that can cause a severe necrotizing myopathy and acute rhabdomyolysis and myoglobinuria. The current update focuses on the mechanisms of statin myotoxicity and the importance of genetic predisposing factors for statin myopathy, as well as the recently described form of necrotizing autoimmune myopathy, which is associated with antibodies to the 3-hydroxy-3-methylglutaryl-coenzyme A reductase enzyme and is responsive to aggressive immunotherapy. Mitochondrial myopathies associated with antiretroviral agents and the pyrimidine nucleoside analogue clevudine, and recent reports of myopathies caused by ingestion of red yeast rice and toxic species of mushrooms are also discussed. [ABSTRACT FROM AUTHOR]

Metabolic myopathies are a clinically and etiologically heterogeneous group of disorders due to defects in muscular energy metabolism. They include glycogen storage diseases, fatty acid oxidation defects, and mitochondrial disorders. The typical manifestations of a metabolic myopathy are exercise-induced myalgias, exercise intolerance, and cramps. Evaluating subjects with such symptoms is not easy because of the frequent lack of clinical features. Exercise tests are, therefore, reliable screening tools. Here, we discuss the possible role of such exercise testing techniques in the diagnostic approach of a patient with suspected metabolic myopathy. [ABSTRACT FROM AUTHOR]

We consider recent developments in disorders affecting three areas of metabolism: glycogen, fatty acids, and the mitochondrial respiratory chain. Among the glycogenoses, new attention has been directed to defects of glycogen synthesis resulting in absence rather than excess of muscle glycogen (“aglycogenosis”). These include defects of glycogen synthetase and defects of glycogenin, the primer of glycogen synthesis. Considerable progress also has been made in our understanding of alterations of glycogen metabolism that result in polyglucosan storage. Among the disorders of lipid metabolism, mutations in the genes encoding two triglyceride lipases acting hand in hand cause severe generalized lipid storage myopathy, one associated with ichthyosis (Chanarin-Dorfman syndrome), the other dominated by juvenile-onset weakness. For the mitochondrial myopathies, we discuss the importance of homoplasmic mitochondrial DNA mutations and review the rapid progress made in our understanding of the coenzyme Q deficiencies, which are often treatable. [ABSTRACT FROM AUTHOR]

Unlabelled: We studied a 3-month-old girl who was admitted to hospital because of respiratory distress. The clinical course was characterized by a rapidly progressive generalized hypotonia with lactic acidosis and she died at 4 months of age. A muscle biopsy showed few ragged-red fibres and lack of histochemical cytochrome c oxidase reaction in all fibres. Enzyme activities of the respiratory chain complexes containing subunits encoded by the mitochondrial DNA (mtDNA) were markedly decreased. A quantitative Southern blot analysis revealed 99% depletion of mtDNA in muscle and normal amounts in blood. There was no family history and the dizygotic twin sister of the patient was no symptomatic.Conclusion: This new case confirms the rapidly fatal evolution associated with severe depletion of muscle mtDNA. [ABSTRACT FROM AUTHOR]

The mitochondrial pathologies are a heterogeneous group of metabolic disorders that are characterized by anomalies of oxidative phosphorylation, especially in the respiratory chain. The diagnosis of these pathologies involves many investigations among which biochemical study is at present the main tool. However, the analysis of the results obtained during such study remains complex and often does not make it possible to conclude clearly if a patient is affected or not by a biochemical and/or bioenergetic deficiency. This arises from two main problems: 1. The determination of control values from the whole set of variable values (affected and unaffected people). 2. The small size of the population studied and the large number of variables collected which present a rather large variability. To cope with these problems, the principal component analysis method is applied to the results obtained during our biochemical studies. This analysis makes it possible for each respiratory chain complex, to distinguish clearly two subsets of the whole population (affected and unaffected people) as well as to detect the variables which are the most discriminative. (Mol Cell Biochem 174: 149–156, 1997) [ABSTRACT FROM AUTHOR]

Mitochondrial inclusion bodies are often described in skeletal muscle of patients suffering diseases termed mitochondrial myopathies. A major component of these structures was discovered as being creatine kinase. Similar creatine kinase enriched inclusion bodies in the mitochondria of creatine depleted adult rat cardiomyocytes have been demonstrated. Structurally similar inclusion bodies are observed in mitochondria of ischemic and creatine depleted rat skeletal muscle. This paper describes the various methods for inducing mitochondrial inclusion bodies in rodent skeletal muscle, and compares their effects on muscle metabolism to the metabolic defects of mitochondrial myopathy muscle. We fed rats with a creatine analogue guanidino propionic acid and checked their soled for mitochondrial inclusion bodies, with the electron microscope. The activity of creatine kinase was analysed by measuring creatine stimulated oxidative phosphorylation in soleus skinned fibres using an oxygen electrode . The guanidino propionic acid-rat soleus mitochondria displayed no creatine stimulation, whereas control soleus did, even though the GPA soled had a five fold increase in creatine kinase protein per mitochondrial protein. The significance of these results in light of their relevance to human mitochondrial myopathies and the importance of altered muscle metabolism in the formation of these crystalline structures are discussed. (Mol Cell Biochem 174: 283–289, 1997) [ABSTRACT FROM AUTHOR]

Currently, considerable research activities are focussing on biochemical, physiological and pathological aspects of the creatine kinase (CK) - phosphorylcreatine (PCr) - creatine (Cr) system (for reviews see [1, 2]), but only little effort is directed towards a thorough investigation of Cr metabolism as a whole. However, a detailed knowledge of Cr metabolism is essential for a deeper understanding of bioenergetics in general and, for example, of the effects of muscular dystrophies, atrophies, CK deficiencies (e.g. in transgenic animals) or Cr analogues on the energy metabolism of the tissues involved. Therefore, the present article provides a short overview on the reactions and enzymes involved in Cr biosynthesis and degradation, on the organization and regulation of Cr metabolism within the body, as well as on the metabolic consequences of 3-guanidinopropionate (GPA) feeding which is known to induce a Cr deficiency in muscle. In addition, the phenotype of muscles depleted of Cr and PCr by GPA feeding is put into context with recent investigations on the muscle phenotype of 'gene knockout' mice deficient in the cytosolic muscle-type M-CK. [ABSTRACT FROM AUTHOR]

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Respiratory chain enzymes were studied in isolated mitochondria of two patients with mitochrondrial myopathy. Both patients had been suffering from chronic progressive external ophthalmoplegia and abnormal muscular fatigability since late childhood. One of the patients exhibited the complete triad of symptoms characteristic of Kearns-Sayre syndrome. Venous lactate levels at rest and during minimal exercise were increased in both patients. Histochemical examination of muscle revealed ragged red fibres and intermingled fibres negative for cytochrome c oxidase. Biochemical studies showed decreased activities of complex I and complex IV of the respiratory chain in both patients. Reduced minus oxidized spectra of mitochondrial cytochromes revealed a decreased content of cytochrome aa in only one patient, but a normal content in the other. A combined deficiency of complexes I and IV in muscle might either be due to a deficiency of a single subunit common to both complexes or to a coincidental deficiency of both complexes expressed either in the same or in different fibres. [ABSTRACT FROM AUTHOR]

Coenzyme Q (CoQ) was measured in serum and muscle of 17 patients with ophthalmoplegia plus (including 5 patients with Kearns-Sayre syndrome), in muscle of 9 patients with neurogenic atrophies, 5 patients with myositis, and 5 patients with progressive muscular dystrophies (including 1 patient with oculopharyngeal dystrophy), and in serum and muscle of normal controls. CoQ was markedly decreased in serum and muscle of 1 patient with Kearns-Sayre syndrome and treatment with CoQ resulted in a significant clinical improvement. The other 4 patients with Kearns-Sayre syndrome and the patients with ophthalmoplegia plus exhibited normal concentrations of CoQ in serum and muscle. CoQ levels in muscle of patients with progressive muscular dystrophies, myositis or neurogenic atrophies were within the normal range. Concentrations of CoQ in serum and muscle of normal controls were independent of age and showed no sex difference. The data indicate that CoQ deficiency might be the specific cause of mitochondrial encephalomyopathy in 1 patient but it was not the underlying defect common to all cases with Kearns-Sayre syndrome and ophthalmoplegia plus, although the possibility of a focal CoQ deficiency affecting only single muscle fibres cannot be excluded. [ABSTRACT FROM AUTHOR]

We describe eight children with complex I deficiency, four of them with an isolated, the other four with an additional deficiency of complex IV. Clinical, chemical and morphological findings were compared from patients with isolated and combined deficiency. In both groups, the age of onset of symptoms was between the 1st day and the 4th month of life. Clinical and biochemical heterogeneity were observed. We found no correlation between residual activity of complex I in muscle, blood lactate level, and severity of clinical symptoms. Newborns presenting with severe lactic acidosis and children with later onset myopathy were seen in both groups. The group with combined complex I deficiency showed a more severe clinical course. By light microscopy ragged red fibres were only found in two patients with combined deficiency. However, by electron microscopy structural alterations of the mitochondria were observed in six out of seven muscle specimens. [ABSTRACT FROM AUTHOR]