Muscle-specific inositide phosphatase (MIP/MTMR14) is reduced with age and its loss accelerates skeletal muscle aging process by altering calcium homeostasis.
We have recently reported that a novel muscle-specific inositide phosphatase (MIP/MTMR14) plays a critical role in [Ca2+]i homeostasis through dephosphorylation of sn-1-stearoyl-2-arachidonoyl phosphatidylinositol (3,5) bisphosphate (PI(3,5)P2). Loss of function mutations in MIP have been identified in human centronuclear myopathy. We developed a MIP knockout (MIPKO) animal model and found that MIPKO mice were more susceptible to exercise-induced muscle damage, a trademark of muscle functional changes in older subjects. We used wild-type (Wt) mice and MIPKO mice to elucidate the roles of MIP in muscle function during aging. We found MIP mRNA expression, MIP protein levels, and MIP phosphatase activity significantly decreased in old Wt mice. The mature MIPKO mice displayed phenotypes that closely resembled those seen in old Wt mice: i) decreased walking speed, ii) decreased treadmill activity, iii) decreased contractile force, and iv) decreased power generation, classical features of sarcopenia in rodents and humans. Defective Ca2+ homeostasis is also present in mature MIPKO and old Wt mice, suggesting a putative role of MIP in the decline of muscle function during aging. Our studies offer a new avenue for the investigation of MIP roles in skeletal muscle function and as a potential therapeutic target to treat aging sarcopenia.
Romero-Suarez
Sandra
S
Muscle Biology Research Group-MUBIG, Schools of Nursing, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
Shen
Jinhua
J
Brotto
Leticia
L
Hall
Todd
T
Mo
Chenglin
C
Valdivia
Héctor H
HH
Andresen
Jon
J
Wacker
Michael
M
Nosek
Thomas M
TM
Qu
Cheng-Kui
CK
Brotto
Marco
M
D000375:Aging / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016922:Cellular Senescence / Q000502:physiology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology*; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D010716:Phosphatidylinositols / Q000502:physiology*; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D055948:Sarcopenia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
D010716:Phosphatidylinositols; C070521:1-stearoyl-2-arachidonoyl phosphatidylinositol; C515634:MTMR14 protein, human; C554751:MTMR14 protein, mouse; D010744:Phosphoric Monoester Hydrolases; D002118:Calcium
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