Abstract
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.
Highlights
Aging is a complex biological process marked by the gradual decline of a multitude of physiological processes/functions that results in death [15]
Our studies showed that MIP is important in the excitation-contraction coupling (ECC) process of skeletal muscle ( influencing store-operated calcium entry (SOCE), calcium (Ca2+) storage and Ca2+ release from the sarcoplasmic reticulum (SR)
All mice tested remained in the actimeter for 40 min, and we found that young wild type (Wt) mice (4-6 month, n=58) walked 280 ± 27 meters, mature Wt (12-14 month, n=20) walked 283 ± 23 meters, and old Wt (22-24 month, n=12) walked 175 ± 32 meters
Summary
Aging is a complex biological process marked by the gradual decline of a multitude of physiological processes/functions that results in death [15]. Normal aging results in sarcopenia, the decreased muscle mass and function that develops despite interventions such as increased physical activity and improved diet [6,7]. While these interventions have proven to be effective in ameliorating the loss of muscle function with age, there is no intervention that can completely prevent or reverse sarcopenia. We measured the cellular expression, concentration, and activity of MIP within muscle fibers with age These findings were correlated with functional outcomes and revealed that key features of sarcopenia manifest in the MIPKO much earlier (12-14 months) than in wild-type mice (22-24 months). The significant decrease in MIP mRNA expression, MIP protein content and MIP activity in normal, old Wt mice along with the striking phenotypic similarities between mature MIPKO and old Wt mice, suggest a putative role of MIP in the aging decline in muscle function
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
