Regulation of Mitochondrial Biogenesis in Skeletal Muscle by CaMK

• Published in: Science (American Association for the Advancement of Science) Vol. 296; no. 5566; pp. 349 - 352
• Main Authors: Wu, Hai, Kanatous, Shane B., Thurmond, Frederick A., Gallardo, Teresa, Isotani, Eiji, Bassel-Duby, Rhonda, Williams, R. Sanders
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for the Advancement of Science 12.04.2002; American Association for the Advancement of Science
• Subjects: Animals; Biological and medical sciences; Blood; Calcium-Calmodulin-Dependent Protein Kinase Type 4; Calcium-Calmodulin-Dependent Protein Kinases - genetics; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cytochromes; DNA Replication; DNA, Mitochondrial - biosynthesis; Electron Transport; Enzymes; Fatty Acids - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Expression Profiling; Human beings; Humans; Lymphocytes; Mammals; Man; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Mitochondria, Muscle - enzymology; Mitochondria, Muscle - metabolism; Muscle Contraction; Muscle Fatigue; Muscle Fibers, Skeletal - ultrastructure; Muscle, Skeletal - enzymology; Muscle, Skeletal - metabolism; Muscle, Skeletal - ultrastructure; Muscles; Oligonucleotide Array Sequence Analysis; Physiological aspects; Promoter Regions, Genetic; Receptors; Signal Transduction; Skeletal muscle; Striated muscle; Striated muscle. Tendons; Transcription Factors - genetics; Transcription Factors - metabolism; Transgenes; Transgenic animals; Transgenic plants; Up-Regulation; Vertebrates: osteoarticular system, musculoskeletal system; United States; Physical exercise; calmodulin-dependent protein kinase; Enzyme; Transferases; Rodentia; Transgenic animal; Gene expression; Striated muscle; Vertebrata; Mitochondria; Regulation(control); Mammalia; Mouse; DNA; Replication; Endurance; Oxidation; Ca
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1071163

Endurance exercise training promotes mitochondrial biogenesis in skeletal muscle and enhances muscle oxidative capacity, but the signaling mechanisms involved are poorly understood. To investigate this adaptive process, we generated transgenic mice that selectively express in skeletal muscle a constitutively active form of calcium/calmodulin-dependent protein kinase IV (CaMKIV*). Skeletal muscles from these mice showed augmented mitochondrial DNA replication and mitochondrial biogenesis, up-regulation of mitochondrial enzymes involved in fatty acid metabolism and electron transport, and reduced susceptibility to fatigue during repetitive contractions. CaMK induced expression of peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1), a master regulator of mitochondrial biogenesis in vivo, and activated the PGC-1 gene promoter in cultured myocytes. Thus, a calcium-regulated signaling pathway controls mitochondrial biogenesis in mammalian cells.