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.