Adenylate kinase 1 deficiency induces molecular and structural adaptations to support muscle energy metabolism.
Genetic ablation of adenylate kinase 1 (AK1), a member of the AK family of phosphotransfer enzymes, disturbs muscle energetic economy and decreases tolerance to metabolic stress, despite rearrangements in alternative high energy phosphoryl transfer pathways. To define the mechanisms of this adaptive response, soleus and gastrocnemius muscles from AK1(-/-) mice were characterized by cDNA array profiling, Western blot and ultrastructural analysis. We demonstrate that AK1 deficiency induces fiber-type specific variation in groups of transcripts involved in glycolysis and mitochondrial metabolism and in gene products defining structural and myogenic events. This was associated with increased phosphotransfer capacities of the glycolytic enzymes pyruvate kinase and 3-phosphoglycerate kinase. Moreover, in AK1(-/-) mice, fast-twitch gastrocnemius, but not slow-twitch soleus, had an increase in adenine nucleotide translocator (ANT) and mitochondrial creatine kinase protein, along with a doubling of the intermyofibrillar mitochondrial volume. These results provide molecular evidence for wide-scale remodeling in AK1-deficient muscles aimed at preservation of efficient energetic communication between ATP producing and utilizing cellular sites.
Janssen
Edwin
E
Department of Cell Biology, Nijmegen Center for Molecular Life Sciences, University Medical Center, University of Nijmegen, The Netherlands.
de Groof
Ad
A
Wijers
Mietske
M
Fransen
Jack
J
Dzeja
Petras P
PP
Terzic
Andre
A
Wieringa
Bé
B
D000263:Adenylate Kinase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism; D005091:Exons; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006720:Homozygote; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D020411:Oligonucleotide Array Sequence Analysis; D010101:Oxygen Consumption; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic
D007527:Isoenzymes; D009124:Muscle Proteins; D012333:RNA, Messenger; D012313:RNA; D000263:Adenylate Kinase; C110939:adenylate kinase 1