Mitochondrial DNA Copy Number Assist with Diagnosis of Vague Myopathy

Although precisely classifying the subgroups of myopathy is important given the differences of their pathophysiology, often the histologic or clinical findings are ambiguous, making it difficult for an accurate diagnosis. Mitochondrial DNA copy number (mtDNA-CN) alterations have been associated with several muscular diseases. In the present study, we investigated the level of mtDNA-CN from myopathy patients to identify the potential of mtDNA-CN as an objective indicator of several cytopathologic changes occurring in the muscle cells. We assessed the mtDNA-CN of 162 myopathy patients from diverse ages and diseases using real-time PCR method, and for the first time, the resultant mtDNA-CN was correlated with histopathologic features. Patients with muscular diseases were expected to show either an increase or decrease of mtDNA-CN but results from the present data show that the patients suffering from muscular diseases seem to generally undergo an increase in mtDNA-CN. In particular, even though there is no significant difference in mtDNA-CN between different age groups, younger individuals tend to experience even more drastic increases. To identify whether there is a significant histological difference between high and low mtDNA-CN group, myopathy patients were subdivided based on the highest normal mtDNA-CN; high mtDNA-CN group showed more instances of mitochondrial accumulation (P<0.01) and intra-mitochondrial inclusion bodies (P<0.01), while low mtDNA-CN group showed more instances of inflammation (P<0.01) and hypertrophy (P<0.01). Furthermore, stratified analysis to adjust for the age factor revealed that the differences between high and low mtDNA-CN group were more dramatic in older adults; high mtDNA-CN showed more instances of mitochondrial accumulation (P<0.01), megamitochondria (P<0.05), and intra-mitochondrial electron dense inclusion (P<0.01) while low mtDNA-CN showed more instances of inflammation (P<0.01) and hypertrophy (P<0.01). The findings of this study therefore suggest that the increase in mtDNA-CN of muscle tissue can indicate the mitochondrial alteration, such as mitochondrial accumulation and megamitochondria, reflecting compensatory cellular reaction against the mitochondrial dysfunction. In contrast, the failure of appropriate compensation, which is expressed as a low mtDNA-CN, leads to various pathologic changes such as inflammation and hypertrophy. The efficiency of the compensatory mechanism is also related with age-dependent disease prevalence; inflammatory myopathy is more prevalent in older individuals with low mtDNA-CN, while non-inflammatory primary myopathy is more prevalent in younger individuals with high mtDNA-CN. In conclusion, we analyzed mtDNA-CN of a massive group of patients and for the first time and the resultant data was correlated with histopathologic changes. The present data indicate the possible use of mtDNA-CN as a quantifiable biomarker of several cytopathologic changes, assisting diagnosis of vague myopathy.