Myeloid Hypoxia-Inducible Factor-1α Is Essential for Skeletal Muscle Regeneration in Mice

Abstract

The outstanding regeneration ability of skeletal muscle is based on stem cells that become activated and develop to myoblasts after myotrauma. Proliferation and growth of myoblasts result in self-renewal of skeletal muscle. In this article, we show that myotrauma causes a hypoxic microenvironment leading to accumulation of the transcription factor hypoxia-inducible factor-1 (HIF-1) in skeletal muscle cells, as well as invading myeloid cells. To evaluate the impact of HIF-1 in skeletal muscle injury and repair, we examined mice with a conditional HIF-1α knockout targeted to skeletal muscle or myeloid cells in a model of soft tissue trauma. No differences in acute trauma size were detected between control and HIF-1α knockout mice. However, muscles of myeloid HIF-1α knockout mice showed a significant delay in myoblast proliferation and growth of regenerating myofibers, in association with decreased expression of cyclooxygenase-2 in HIF-1α–deficient myeloid cells. Moreover, the removal of necrotic cell debris and the regeneration of endothelial cell structure were impaired in myeloid HIF-1α knockout mice that showed delayed invasion of macrophages to the injury site. Our findings for the first time, to our knowledge, demonstrate that myeloid HIF-1α is required for adequate skeletal muscle regeneration.

Myeloid HIFs Are Dispensable for Resolution of Inflammation during Skeletal Muscle Regeneration

“…To assess a definitive role of HIF1 in myeloid cells, further analysis at later time points of regeneration (i.e., 3 wk) is required (31). Moreover, the study by Scheerer et al (30) reported no alteration of myeloid HIF-1a deletion on MP infiltration or on MP polarization, which is in agreement with the data presented in this article in two models of sterile inflammation. Scheerer et al's (30) study reported a transient delay in the number of F4/80 + cells, suggesting a defect in the proliferation of some MPs in the HIF1aKO strain.…”

“…Besides its role in hypoxia and in inflammation under normoxic conditions, HIF-1 is involved in skeletal muscle homeostasis and physiology (43,(49)(50)(51)(52). Recently, it has been claimed that myeloid HIF-1a was essential for skeletal muscle regeneration after a soft trauma (30). Our results, showing no alteration of skeletal muscle regeneration in mice depleted for myeloid HIFs in two different models of sterile injury dispute this assertion.…”

“…To determine whether the tissue injured with CTX was hypoxic, we used pimonidazole labeling (30). Eleven, 67, and 55% of CD45 + cells extracted from regenerating WT muscle were hypoxic 2, 4, and 8 d after injection of CTX in the TA muscle, respectively (Supplemental Fig.…”

“…Thus, postinjury skeletal muscle regeneration provides an excellent paradigm to study events related to the resolution of sterile inflammation. Recently, Scheerer et al (30) claimed that myeloid HIF-1a is essential for skeletal muscle regeneration, using a model of soft-tissue trauma of the mouse hindlimb. However, according to the relevant markers for evaluation of skeletal muscle regeneration presented in this study, deletion of HIF-1a in MPs induces only a delay in short-term period of skeletal muscle regeneration (30).…”

“…Recently, Scheerer et al (30) claimed that myeloid HIF-1a is essential for skeletal muscle regeneration, using a model of soft-tissue trauma of the mouse hindlimb. However, according to the relevant markers for evaluation of skeletal muscle regeneration presented in this study, deletion of HIF-1a in MPs induces only a delay in short-term period of skeletal muscle regeneration (30). Furthermore, the resolution of inflammation, which is essential for efficient skeletal muscle regeneration (22), was not investigated.…”