Myosin Binding Protein-C Slow Phosphorylation is Altered in Duchenne Dystrophy and Arthrogryposis Myopathy in Fast-Twitch Skeletal Muscles.
Myosin Binding Protein-C slow (sMyBP-C), encoded by MYBPC1, comprises a family of regulatory proteins of skeletal muscles that are phosphorylated by PKA and PKC. MYBPC1 missense mutations are linked to the development of Distal Arthrogryposis-1 (DA-1). Although structure-function details for this myopathy are evolving, function is undoubtedly driven by sequence variations and post-translational modifications in sMyBP-C. Herein, we examined the phosphorylation profile of sMyBP-C in mouse and human fast-twitch skeletal muscles. We used Flexor Digitorum Brevis (FDB) isolated from young (~2-months old) and old (~14-months old) wild type and mdx mice, and human Abductor Hallucis (AH) and gastrocnemious muscles carrying the DA-1 mutations. Our results indicate both constitutive and differential phosphorylation of sMyBP-C in aged and diseased muscles. We report a 7-35% reduction in the phosphorylation levels of select sites in old wild type and young or old mdx FDB mouse muscles, compared to young wild type tissue. Similarly, we observe a 30-70% decrease in the phosphorylation levels of all PKA and PKC phospho-sites in the DA-1 AH, but not gastrocnemius, muscle. Overall, our studies show that the phosphorylation pattern of sMyBP-C is differentially regulated in response to age and disease, suggesting that phosphorylation plays important roles in these processes.
University of Maryland, School of Medicine, Department of Biochemistry and Molecular Biology, Baltimore, MD, USA.
Maegen A
MA
Ackermann
University of Maryland, School of Nursing, Baltimore, MD, USA.
Christopher W
CW
Ward
Washington University, School of Medicine, Department of Neurology, St. Louis, MO, USA.
Christina
C
Gurnett
University of Maryland, School of Medicine, Department of Biochemistry and Molecular Biology, Baltimore, MD, USA.
Aikaterini
A
Kontrogianni-Konstantopoulos
D000293:Adolescent; D000375:Aging / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001176:Arthrogryposis / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D008297:Male; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008969:Molecular Sequence Data; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D000099163:Myosin Binding Protein C