Abstract
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 gamma 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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Calcium-Calmodulin-Dependent Protein Kinase Type 4
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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DNA Replication
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DNA, Mitochondrial / biosynthesis
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Electron Transport
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Fatty Acids / metabolism
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Gene Expression
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Gene Expression Profiling
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mitochondria, Muscle / enzymology
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Mitochondria, Muscle / metabolism*
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Muscle Contraction
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Muscle Fatigue
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Muscle Fibers, Skeletal / ultrastructure
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Muscle, Skeletal / enzymology
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Muscle, Skeletal / metabolism*
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Muscle, Skeletal / ultrastructure
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Oligonucleotide Array Sequence Analysis
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Promoter Regions, Genetic
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Signal Transduction
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transgenes
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Up-Regulation
Substances
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DNA, Mitochondrial
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Fatty Acids
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Transcription Factors
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peroxisome-proliferator-activated receptor-gamma coactivator-1
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Calcium-Calmodulin-Dependent Protein Kinase Type 4
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Calcium-Calmodulin-Dependent Protein Kinases
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Camk4 protein, mouse