Mitochondrial dysfunction in myofibrillar myopathy

Abstract

'Myofibrillar myopathy' defines a myopathic condition with focal myofibrillar destruction and accumulation of degraded myofibrillar elements. Despite the fact that a number of mutations in different genes as well as cytotoxic agents lead to the disease, abnormal accumulation of desmin is a typical, common feature. Pathological changes of mitochondrial morphology and function have been observed in animal models with intermediate filament pathology. Therefore, in the present study we tested for mitochondrial pathology in skeletal muscle of five patients with the pathohistological diagnosis of myofibrillar myopathy. Screening for large-scale mtDNA deletions and the frequent MERRF (myoclonic epilepsy; ragged red fibres) and MELAS (mitochondrial encephalomyopathy; lactic acidosis; stroke) point mutations was negative in all patients. Histologically, all muscle biopsies showed nonspecific abnormalities of the oxidative/mitochondrial enzyme stainings (histochemistry for reduced nicotinamide adenine dinucleotide, succinic dehydrogenase, cytochrome c oxidase), only one of them had ragged red fibres and a significant number of cytochrome c oxidase-negative fibres. Upon biochemical investigation, four of our patients showed pathologically low respiratory chain complex I activities. Only one of our patients had a pathologically low complex IV activity, while the measurements of the others were within low normal range. The single patient with pathological values for both complex I and IV was the one with the clear histological hallmarks (ragged red and cytochrome c oxidase-negative fibres) of mitochondrial pathology. She also was the only patient with clinical signs hinting at a mitochondrial disorder. Together with data from observations in desmin- and plectin-deficient mice, our results support the view that desmin intermediate filament pathology in these cases is closely linked to mitochondrial dysfunction in skeletal muscle.

Mitochondrial Dysfunction and Apoptosis Underlie the Pathogenic Process in α-B-Crystallin Desmin-Related Cardiomyopathy

“…In the last decade, using a number of different approaches including loss of function, it has become apparent that the cytoskeleton in general and the intermediate filaments in particular play an important role in mitochondrial localization and transport. 9,12,13 In our previous analyses of cardiac tissue from CryAB R120G mice, we noted that disruption of the desmin network occurred early in 3-month adults with detectable aggregation of desmin and CryAB. 5 To assess whether mitochondrial ultrastructure was also affected by CryAB R120G expression, we examined cardiomyocyte ultrastructure at 6 weeks, when the sarcomeric architecture is fully developed (Figure 2).…”

“…Mitochondrial organization is rigidly controlled in both skeletal and cardiac myocytes and depends on the integrity of the cytoskeleton. 9 To explore whether early pathological processes involved mitochondrial dysfunction and to determine the pathogenic basis for the heart failure observed in the CryAB R120G mice, we have now defined the acute and chronic effects of cardiomyocyte CryAB R120G expression in vitro and in vivo. CryAB R120G expression quickly leads to visible aggregates, and their accumulation results in deficits in contractile behavior as the cell contracts at high rates.…”

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

“…In DRC mice expressing either D7‐Des or CryAB R120G , mitochondrial spatial organization was highly perturbed, and the myofibrils were interspersed with electron‐dense aggregates. Similarly, tissue biopsy samples from patients diagnosed with myofibrillar myopathies show abnormal mitochondrial enzyme staining and have reduced mitochondrial complex‐I activities 15. Despite extensive studies, the genetic pathologies for the DRCs are only partially defined and the pathogenic sequelae remain obscure.…”

Cardiomyopathies Associated with Myofibrillar Myopathies

“…Structural studies of intracellular arrangements of mitochondria into functional complexes with myofibrils and sarcoplasmic reticulum demonstrate their importance in mitochondrial oxydative activity and membrane permeability (Andrienko et al, 2003;Appaix et al, 2003). There are findings with pathological respiratory chain enzyme activities in patients with MFM (Reimann et al, 2003). Desmin intermediate filaments (IFs) might participate in mitochondrial positioning to areas of high energy demand, respiratory function, and calcium cycling in cardiac and skeletal muscle (Capetanaki, 2002).…”