Influence of hypoxic stimulation on angiogenesis and satellite cells in mouse skeletal muscle

Abstract

We clarified in our previous study that hypoxic training promotes angiogenesis in skeletal muscle, but the mechanism of angiogenesis in skeletal muscle remains unknown. In this study, we investigated the influence of differences in hypoxia exposure on angiogenesis in skeletal muscles at differing ages and metabolic characteristics at which the production of reactive oxygen species and nitric oxide may differ. Ten-week-old (young) and 20-month-old (old) mice were separated into control (N), continuous hypoxia (H), and intermittent hypoxia (IH) groups. The H group was exposed to 16% O2 hypoxia for 5 days and the IH group was exposed to 16% O2 hypoxia at one-hour intervals during the light period for 5 days. After completion of hypoxia exposure, the soleus and gastrocnemius muscles were immediately excised, and mRNA expression of angiogenesis- and satellite cell-related genes was investigated using real-time RT-PCR. In addition, muscle fiber type composition, muscle fiber area, number of satellite cells, and capillary density were measured immunohistochemically. In the young soleus muscle, the muscle fiber area was decreased in the H group, and mRNA expression of satellite cell activation-related MyoD, MHCe, and BDNF was significantly increased. On the other hand, in the old soleus muscle, nNOS and VEGF-A mRNA expression, and the capillary density were significantly increased in the H group. In the superficial portion of the gastrocnemius, mRNA expression of FGF2, an angiogenic factor secreted by satellite cells, was significantly increased in the young IH group. In addition, a positive correlation between VEGF-A mRNA expression and nNOS mRNA expression in the soleus muscle and eNOS mRNA expression in the superficial portion of the gastrocnemius was noted. These data demonstrated that age, hypoxia exposure method and muscle metabolic characteristics are related, which results in significant differences in angiogenesis.

Exercise-mediated angiogenesis

“…In addition, there is renewed interest in the role of perivascular cells in regulating adaptive angiogenesis, providing a paracrine influence of e.g. pericytes and satellite cells on the endothelium [25] offering an additional site for sensing both chemical and physical changes in the local environment and hence influencing the response to exercise. However, the role of endothelial chemotransduction in driving angiogenesis is extensively covered in the literature, largely driven by tumour angiogenesis investigations; the main players in skeletal muscle are summarised in [26] and some new angles explored in [8].…”

Acute environmental hypoxia potentiates satellite cell‐dependent myogenesis in response to resistance exercise through the inflammation pathway in human

“…23 In addition, the role of hypoxia-inducible factor-1 alpha (HIF-1α) in those events is still unclear. [26][27][28] Mechanistically, IL-6 is responsible for STAT3 translocation in the nucleus. 24,25 On the other hand, acute hypoxia promotes myogenic differentiation and induces nuclear factor kappa B (NF-κB)/IL-6/STAT3 and Hippo pathway activation, both known to activate the myogenic program.…”

“…On the one hand, chronic hypoxia is known to increase the expression of myogenesis inhibitors, myostatin and basic helix‐loop‐helix family member E40 (BHLHE40) . On the other hand, acute hypoxia promotes myogenic differentiation and induces nuclear factor kappa B (NF‐κB)/IL‐6/STAT3 and Hippo pathway activation, both known to activate the myogenic program . Mechanistically, IL‐6 is responsible for STAT3 translocation in the nucleus .…”

Prolyl hydroxylase domain 2 reduction enhances skeletal muscle tissue regeneration after soft tissue trauma in mice

“…Furthermore, myogenic regulatory factors (MRF) are expressed by proliferating muscle cells during specific differentiation states [19,25]. HIF-1 is able to activate the expression of Pax7 through direct interaction with the Pax7 promoter [26], MyoD and myogenin are targets of hypoxia likewise [27].…”