Six1 homeoprotein drives myofiber type IIA specialization in soleus muscle.
Adult skeletal muscles are composed of slow and fast myofiber subtypes which each express selective genes required for their specific contractile and metabolic activity. Six homeoproteins are transcription factors regulating muscle cell fate through activation of myogenic regulatory factors and driving fast-type gene expression during embryogenesis.



We show here that Six1 protein accumulates more robustly in the nuclei of adult fast-type muscles than in adult slow-type muscles, this specific enrichment takes place during perinatal growth. Deletion of Six1 in soleus impaired fast-type myofiber specialization during perinatal development, resulting in a slow phenotype and a complete lack of Myosin heavy chain 2A (MyHCIIA) expression. Global transcriptomic analysis of wild-type and Six1 mutant myofibers identified the gene networks controlled by Six1 in adult soleus muscle. This analysis showed that Six1 is required for the expression of numerous genes encoding fast-type sarcomeric proteins, glycolytic enzymes and controlling intracellular calcium homeostasis. Parvalbumin, a key player of calcium buffering, in particular, is a direct target of Six1 in the adult myofiber.



This analysis revealed that Six1 controls distinct aspects of adult muscle physiology in vivo, and acts as a main determinant of fast-fiber type acquisition and maintenance.
INSERM U1016, Institut Cochin, Paris, 75014 France ; CNRS UMR 8104, Paris, 75014 France ; Université Paris Descartes, Sorbonne Paris Cité, Paris, 75014 France ; Division of Integrative Pathophysiology, Proteo-Science Center, Graduate School of Medicine, Ehime University, Ehime, Japan.
Iori
I
Sakakibara
INSERM U1016, Institut Cochin, Paris, 75014 France ; CNRS UMR 8104, Paris, 75014 France ; Université Paris Descartes, Sorbonne Paris Cité, Paris, 75014 France.
Maud
M
Wurmser
INSERM U1016, Institut Cochin, Paris, 75014 France ; CNRS UMR 8104, Paris, 75014 France ; Université Paris Descartes, Sorbonne Paris Cité, Paris, 75014 France.
Matthieu
M
Dos Santos
Laboratoire de Physique Statistique, CNRS, Université P. et M. Curie, Université D. Diderot, École Normale Supérieure, Paris, 75005 France.
Marc
M
Santolini
Nestlé Institute of Health Sciences SA, EPFL Innovation Park, Lausanne, Switzerland.
Serge
S
Ducommun
INSERM U1016, Institut Cochin, Paris, 75014 France ; CNRS UMR 8104, Paris, 75014 France ; Université Paris Descartes, Sorbonne Paris Cité, Paris, 75014 France.
Romain
R
Davaze
INSERM U1016, Institut Cochin, Paris, 75014 France ; CNRS UMR 8104, Paris, 75014 France ; Université Paris Descartes, Sorbonne Paris Cité, Paris, 75014 France.
Anthony
A
Guernec
Nestlé Institute of Health Sciences SA, EPFL Innovation Park, Lausanne, Switzerland.
Kei
K
Sakamoto
INSERM U1016, Institut Cochin, Paris, 75014 France ; CNRS UMR 8104, Paris, 75014 France ; Université Paris Descartes, Sorbonne Paris Cité, Paris, 75014 France.
Pascal
0000-0001-7795-0029
P
Maire
D000818:Animals; D002118:Calcium / Q000378:metabolism; D017353:Gene Deletion; D053263:Gene Regulatory Networks; D006019:Glycolysis; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D059467:Transcriptome
D018398:Homeodomain Proteins; C490947:Six1 protein, mouse; D018995:Myosin Heavy Chains; D002118:Calcium
Myosin heavy chain; Pvalb; Six1; Skeletal muscle; Slow and fast myofibers; Soleus