Plasticity in skeletal, cardiac, and smooth muscle - Invited review: Contractile activity-induced mitochondrial biogenesis in skeletal muscle

Invited Review: Contractile activity-induced mitochondrial biogenesis in sk eletal muscle. J Appl Physiol 90: 1137-1157, 2001.-Chronic contractile acti vity produces mitochondrial biogenesis in muscle. This adaptation results i n a significant shift in adenine nucleotide metabolism, with attendant impr ovements in fatigue resistance. The vast majority of mitochondrial proteins are derived from the nuclear genome, necessitating the transcription of ge nes, the translation of mRNA into protein, the targeting of the protein to a mitochondrial compartment via the import machinery, and the assembly of m ultisubunit enzyme complexes in the respiratory chain or matrix. Putative s ignals involved in initiating this pathway of gene expression in response t o contractile activity likely arise from combinations of accelerations in A TP turnover or imbalances between mitochondrial ATP synthesis and cellular ATP demand, and Ca2+ fluxes. These rapid events are followed by the activat ion of exercise-responsive kinases, which phosphorylate proteins such as tr anscription factors, which subsequently bind to upstream regulatory regions in DNA, to alter transcription rates. Contractile activity increases the m RNA levels of nuclear-encoded proteins such as cytochrome c and mitochondri al transcription factor A (Tfam) and mRNA levels of upstream transcription factors like c-jun and nuclear respiratory factor-1 (NRF-1). mRNA level cha nges are often most evident during the postexercise recovery period, and th ey can occur as a result of contractile activity-induced increases in trans cription or mRNA stability. Tfam is imported into mitochondria and controls the expression of mitochondrial DNA (mtDNA). mtDNA contributes only 13 pro tein products to the respiratory chain, but they are vital for electron tra nsport and ATP synthesis. Contractile activity increases Tfam expression an d accelerates its import into mitochondria, resulting in increased mtDNA tr anscription and replication. The result of this coordinated expression of t he nuclear and the mitochondrial genomes, along with poorly understood chan ges in phospholipid synthesis, is an expansion of the muscle mitochondrial reticulum. Further understanding of 1) regulation of mtDNA expression, 2) u pstream activators of NRF-1 and other transcription factors, 3) the identit y of mRNA stabilizing proteins, and 4) potential of contractile activity-in duced changes in apoptotic signals are warranted.