Hypoxia‐inducible factor 1α (HIF‐1α) is a major determinant in the enhanced function of muscle‐derived progenitors from MRL/MpJ mice

Abstract

Although the mouse strain Murphy Roths Large (MRL/MpJ) possesses high regenerative potential, the mechanism of tissue regeneration, including skeletal muscle, in MRL/MpJ mice after injury is still unclear. Our previous studies have shown that muscle‐derived stem/progenitor cell (MDSPC) function is significantly enhanced in MRL/MpJ mice when compared with MDSPCs isolated from age‐matched wild‐type (WT) mice. Using mass spectrometry–based proteomic analysis, we identified increased expression of hypoxia‐inducible factor (HIF) 1α target genes (expression of glycolytic factors and antioxidants) in sera from MRL/MpJ mice compared with WT mice. Therefore, we hypothesized that HIF‐1α promotes the high muscle healing capacity of MRL/MpJ mice by increasing the potency of MDSPCs. We demonstrated that treating MRL/MpJ MDSPCs with dimethyloxalylglycine and CoCl2 increased the expression of HIF‐1α and target genes, including angiogenic and cell survival genes. We also observed that HIF‐1α activated the expression of paired box (Pax)7 through direct interaction with the Pax7 promoter. Furthermore, we also observed a higher myogenic potential of MDSPCs derived from prolyl hydroxylase (Phd) 3—knockout (Phd3−/−) mice, which displayed higher stability of HIF‐1α. Taken together, our findings suggest that HIF‐1α is a major determinant in the increased MDSPC function of MRL/MpJ mice through enhancement of cell survival, proliferation, and myogenic differentiation.—Sinha, K. M., Tseng, C., Guo, P., Lu, A., Pan, H., Gao, X., Andrews, R., Eltzschig, H., Huard, J. Hypoxia‐inducible factor 1α (HIF‐1α) is a major determinant in the enhanced function of muscle‐derived progenitors from MRL/MpJ mice. FASEB J. 33, 8321–8334 (2019). http://www.fasebj.org

The MRL/MpJ Mouse Strain Is Not Protected From Muscle Atrophy and Weakness After Rotator Cuff Tear

“…14,15 Increased glycolytic gene expression was also observed in the cultured cells. 14 Using a cardiotoxin injury model, gastrocnemius muscles of MRL mice had reduced macrophage signal intensity and fewer IgG + fibers through 5 days after injury. 15 By 30 days, MRL mice had a greater number of Pax7 + cells per myofiber, and increased dystrophin + muscle fibers.…”

“…14,15 The elevated levels of HIF1α resulted in several changes in vitro that generally correlate with improved muscle healing in vivo, including increased expression of the myogenic transcription factor Pax7, increased cell proliferation, and an induction of cell survival and reactive oxygen species buffering genes. 14,15 Increased glycolytic gene expression was also observed in the cultured cells. 14 Using a cardiotoxin injury model, gastrocnemius muscles of MRL mice had reduced macrophage signal intensity and fewer IgG + fibers through 5 days after injury.…”

“…11,12 MRL mice also display reduced muscle fibrosis in a γ-sarcoglycan-deficient model of muscular dystrophy, 13 and muscle progenitor cells from MRL mice display increased rates of proliferation and myogenesis in vitro. 14,15 However, the MRL strain does not display enhanced tissue healing for every organ system and type of injury, with no differences noted between MRL mice and controls in dorsal skin healing following punch injury, nor in cardiac healing following infarct. 16,17 While there are previous findings that suggest that MRL mice might be protected against atrophy in the context of a rotator cuff tear, the rotator cuff demonstrates more pronounced degeneration after tendon rupture than other muscle groups, 18 and there is a reduced myogenic capacity of satellite cells from the rotator cuff compared with satellite cells from other limb muscles.…”

“…MRL mice have an absence of articular cartilage degeneration and improved regeneration and after joint injury, and superior mechanical properties and healing after tendon injury . MRL mice also display reduced muscle fibrosis in a γ‐sarcoglycan‐deficient model of muscular dystrophy, and muscle progenitor cells from MRL mice display increased rates of proliferation and myogenesis in vitro . However, the MRL strain does not display enhanced tissue healing for every organ system and type of injury, with no differences noted between MRL mice and controls in dorsal skin healing following punch injury, nor in cardiac healing following infarct …”

High bone microarchitecture, strength, and resistance to bone loss in MRL/MpJ mice correlates with activation of different signaling pathways and systemic factors

“…4 It has been reported that the MRL/MpJ mice have accelerated ear punch closure, demonstrating a remarkable capacity for cartilaginous wound closure. 16,17 Previous studies demonstrated that MRL/MpJ mice can heal a full-thickness trochlear groove cartilage injury, whereas C57BL/6J mice do not. It has been found that this strain of mice also exhibits excellent healing in amputated digit tips, 6,7 peripheral nerves, 8 alkali-burned corneas, 9 and cardiac wounds, and also shows enhanced cartilage regeneration.…”