MITOCHONDRIAL INTERMEMBRANE INCLUSION-BODIES - THE COMMON DENOMINATORBETWEEN HUMAN MITOCHONDRIAL MYOPATHIES AND CREATINE DEPLETION, DUE TOIMPAIRMENT OF CELLULAR ENERGETICS

Mitochondrial inclusion bodies are often described in skeletal muscle of patients suffering diseases termed mitochondrial myopathies. A majo r component of these structures was discovered as being mitochondrial creatine kinase. Similar creatine kinase enriched inclusion bodies in the mitochondria of creatine depleted adult rat cardiomyocytes have be en demonstrated. Structurally similar inclusion bodies are observed in mitochondria of ischemic and creatine depleted rat skeletal muscle. T his paper describes the various methods for inducing mitochondrial inc lusion 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 solei for mitochondrial inclusion bodies, with the e lectron microscope. The activity of creatine kinase was analysed by me asuring creatine stimulated oxidative phosphorylation in soleus skinne d fibres using an oxygen electrode. The guanidino propionic acid-rat s oleus mitochondria displayed no creatine stimulation, whereas control soleus did, even though the GPA solei had a five fold increase in crea tine kinase protein per mitochondrial protein. The significance of the se results in light of their relevance to human mitochondrial myopathi es and the importance of altered cell energetics and metabolism in the formation of these crystalline structures are discussed.