Muscle-specific inositide phosphatase (MIP/MTMR14) is reduced with age and its loss accelerates skeletal muscle aging process by altering calcium homeostasis

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.

Vac14 Protein Multimerization Is a Prerequisite Step for Fab1 Protein Complex Assembly and Function

“…However, it should be stressed that these functions are not universal to all organisms or cell types; for example, autophagy defects are only perceived in higher eukaryotes but not in yeast (1). Interestingly, PtdIns(3,5)P 2 has emerged as an apparent novel regulator of various Ca 2ϩ channels, including the ryanodine receptor in cardiac tissue and the lysosomal TRPML1 channel defective in mucolipodosis type IV (12)(13)(14).…”

Aging, sarcopenia and store-operated calcium entry

“…5 If this situation becomes chronic, the SR would naturally have less calcium available to be released for contractions, ultimately translating into less contractile force, which, when coupled with the aging-related shift of faster into slower myosin/myosin light chain isoforms, 7 unequivocally results in decreased muscle power. These complex modifications might help explain the puzzling fact that atrophy alone can only explain a part of the totality of power loss in aged muscles 8,9 as well as open the doors of our scientific inquiry to new signaling pathways that might contribute to the complex phenotype of the aged muscle. [8][9][10][11][12][13] But this is not the entire tale of SOCE in aging muscles.…”

“…These complex modifications might help explain the puzzling fact that atrophy alone can only explain a part of the totality of power loss in aged muscles 8,9 as well as open the doors of our scientific inquiry to new signaling pathways that might contribute to the complex phenotype of the aged muscle. [8][9][10][11][12][13] But this is not the entire tale of SOCE in aging muscles. Recent studies in our lab suggest that SOCE and extracellular calcium entry might also play roles in modulating muscle myogenic differentiation as well as muscle adaptation to stress, such as heat shock.…”

Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

“…Fourth, declines in expression of phosphatases or kinases with age may contribute to the onset and/or progression of sarcopenia. For example, myotubularin‐releated protein 14 displays reduced expression with age in mice and its loss accelerates sarcopenia 58. Lastly, alterations in expression of phosphatases or kinases with activity may contribute to individual differences in muscular adaptation to exercise.…”