Calcineurin Co-regulates contractile and metabolic components of slow muscle phenotype.
Activation of the transcription factor nuclear factor of activated T cells by the calcium-sensitive serine/threonine phosphatase calcineurin has been proposed as one of the molecular mechanisms by which motor nerve activity establishes the slow muscle phenotype. To investigate whether the calcineurin pathway can regulate the large spectrum of slow muscle characteristics in vivo, we treated rats for three weeks with cyclosporin A (an inhibitor of calcineurin). In soleus (slow muscle), but not in plantaris (fast muscle), the proportion of slow myosin heavy chain (MHC-1) and slow sarcoplasmic reticulum ATPase (SERCA2a) was decreased, whereas that of fast MHC (MHC-2A) and fast SERCA1 increased, indicating a slow to fast contractile phenotype transition. Cytosolic isoforms of creatine kinase and lactate dehydrogenase (most abundant in fast fibers), as well as mitochondrial creatine kinase and citrate synthase activities (elevated in fast/oxidative fibers) were dose dependently increased by cyclosporin A treatment in soleus muscle, with no change in plantaris. Calcineurin catalytic subunit was more abundant in soleus muscle fibers compared with plantaris. Taken together these results suggest that the calcineurin pathway co-regulates a set of multigenic protein families involved in the transition between slow oxidative (type I) to fast oxidative (type IIa) phenotype in soleus muscle.
Bigard
X
X
Unité de Bioénergétique et Environnement, Centre de Recherches du Service de Santé des Armées, Avenue du Maquis du Grésivaudan, 38702, La Tronche Cedex, France.
Sanchez
H
H
Zoll
J
J
Mateo
P
P
Rousseau
V
V
Veksler
V
V
Ventura-Clapier
R
R
D000251:Adenosine Triphosphatases / Q000096:biosynthesis; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D019703:Calcineurin / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis; D002196:Capillaries / Q000378:metabolism; D002950:Citrate (si)-Synthase / Q000378:metabolism; D016572:Cyclosporine / Q000097:blood / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism; D010641:Phenotype; D020033:Protein Isoforms / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
C506945:Atp2a1 protein, rat; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D016572:Cyclosporine; D002950:Citrate (si)-Synthase; D019703:Calcineurin; D000251:Adenosine Triphosphatases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018995:Myosin Heavy Chains; D000252:Calcium-Transporting ATPases