Mitochondrial Myopathies: Diagnosis, Exercise Intolerance, and Treatment Options MARK A. TARNOPOLSKY and SANDEEP RAHA McMaster University Medical Center, Hamilton, Ontario, CANADA ABSTRACT TARNOPOLSKY, M. A., and S. RAHA. Mitochondrial Myopathies: Diagnosis, Exercise Intolerance, and Treatment Options. Med. Sci. Sports Exerc., Vol. 37, No. 12, pp. 2086 –2093, 2005. Mitochondrial myopathies are caused by genetic mutations that directly influence the functioning of the electron transport chain (ETC). It is estimated that 1 of 8000 people have pathology inducing mutations affecting mitochondrial function. Diagnosis often requires a multifaceted approach with measurements of serum lactate and pyruvate, urine organic acids, magnetic resonance spectroscopy (MRS), muscle histology and ultrastructure, enzymology, genetic analysis, and exercise testing. The ubiquitous distribution of the mitochondria in the human body explains the multiple organ involvement. Exercise intolerance is a common but often an overlooked hallmark of mitochondrial myopathies. The muscle consequences of ETC dysfunction include increased reliance on anaerobic metabolism (lactate generation, phosphocreatine degradation), enhanced free radical produc- tion, reduced oxygen extraction and electron flux through ETC, and mitochondrial proliferation or biogenesis (see article by Hood in current issue). Treatments have included antioxidants (vitamin E, alpha lipoic acid), electron donors and acceptors (coenzyme Q10, riboflavin), alternative energy sources (creatine monohydrate), lactate reduction strategies (dichloroacetate) and exercise training. Exercise is a particularly important modality in diagnosis as well as therapy (see article by Taivassalo in current issue). Increased awareness of these disorders by exercise physiologists and sports medicine practitioners should lead to more accurate and more rapid diagnosis and the opportunity for therapy and genetic counseling. Key Words: MUSCLE, MITOCHONDRIA, FREE RADICALS, ANTIOXIDANT THERAPY, ELECTRON TRANSPORT CHAIN T he mitochondria are considered a form of evolution- ary parasite felt to be an ancestor of purple photo- synthetic bacteria that invaded a proto eukaryotic cell approximately one billion years ago as the earth’s environ- ment became more oxidative (20). The symbiotic relation- ship allowed for enhanced aerobic adenosine triphosphate (ATP) delivery and oxygen detoxification in exchange for residence within the proto eukaryotic cell. Throughout evo- lution, the mitochondria have lost many of the genes en- coding for structural and functional proteins to the nuclear genome, yet they retained a bacterial-like circular genome. In humans, the mitochondrial genome is composed of 16,569 base pairs and encodes for 22 tRNA, 2 rRNA, and 13 polypeptide subunits (Fig. 1). In contrast to nuclear DNA (nDNA), where intronic sequences make up most of the genetic material, the mitochondrial DNA (mtDNA) is pre- dominately composed of exons, with a small noncoding region to which regulatory factors bind (transcription factor A (Tfam), single strand DNA binding protein (SSB), and so on). The mitochondrial genome is replicated during poly- cistronic (bacterial-like) mechanism and is not linked to the cell cycle. As a consequence, mitochondrial biogenesis can occur in terminally differentiated cells (e.g., skeletal mus- cle) in response to stimuli such as exercise. Two to ten copies of mitochondrial DNA are found per mitochondria and a single cell can have many thousands of mitochondria (e.g., a single Vastus lateralis muscle cell can have many thousands of mitochondria). Mitochondrial DNA shows maternal inheritance. Fre- quent polymorphisms are found in mitochondrial DNA with approximately 50 base pairs differing between two individ- uals. Most polymorphisms have no biological or genetic consequences, yet some may be partially linked to inherited traits such as oxygen consumption (1,34) and exercise ca- pacity (34). In contrast to benign polymorphisms, patho- logic mutations can also occur, which affect a critical func- tion of the mitochondria, and these can range from type 2 diabetes (24,44) and deafness (18,30), to severe disorders such as mitochondrial DNA depletion (35) and Leigh’s disease (11), resulting in death during infancy. The inheri- tance of pathologic mutations usually follows a unique pattern termed “heteroplasmy.” Heteroplasmy refers to the proportion of mutant to wild-type mitochondrial genomes within a cell. In contrast to Mendelian genetics, where a mutation is either heterozygous or homozygous, the propor- tion of mutant to wild-type mitochondria (heteroplasmy) can range from 99:1 to 1:99. Heteroplasmy segregates within and between tissues and this is called “replicative segregation” (Fig. 2). Consequently, the phenotypic mani- festations of mitochondrial disease can vary between tissues or organs (i.e., brain: intractable seizures; or muscle: pro- found exercise intolerance). To a first approximation, the Address for correspondence: Mark A. Tarnopolsky, Departments of Pedi- atrics and Medicine, Division of Neurology and Rehabilitation–Rm 4U4, McMaster University Medical Center, Hamilton Health Sciences, 1200 Main Street West, Hamilton, Ontario, Canada, L8N 3Z5; E-mail: tarnopol@mcmaster.ca. Submitted for publication December 2004. Accepted for publication April 2005. 0195-9131/05/3712-2086/0 MEDICINE & SCIENCE IN SPORTS & EXERCISE ® Copyright © 2005 by the American College of Sports Medicine DOI: 10.1249/01.mss.0000177341.89478.06 2086