Skeletal myofiber vascular endothelial growth factor is required for the exercise training‐induced increase in dentate gyrus neuronal precursor cells

Abstract

Exercise signals neurogenesis in the dentate gyrus of the hippocampus. This phenomenon requires vascular endothelial growth factor (VEGF) originating from outside the blood-brain barrier, but no cellular source has been identified. Thus, we hypothesized that VEGF produced by skeletal myofibers plays a role in regulating hippocampal neuronal precursor cell proliferation following exercise training. This was tested in adult conditional skeletal myofiber-specific VEGF gene-ablated mice (VEGF ) by providing VEGF and non-ablated (VEGF ) littermates with running wheels for 14 days. Following this training period, hippocampal cerebral blood flow (CBF) was measured by functional magnetic resonance imaging (fMRI), and neuronal precursor cells (BrdU+/Nestin+) were detected by immunofluorescence. The VEGF trained group showed improvements in both speed and endurance capacity in acute treadmill running tests (P < 0.05). The VEGF group did not. The number of proliferating neuronal precursor cells was increased with training in VEGF (P < 0.05) but not in VEGF mice. Endothelial cell (CD31+) number did not change in this region with exercise training or skeletal myofiber VEGF gene deletion. However, resting blood flow through the hippocampal region was lower in VEGF mice, both untrained and trained, than untrained VEGF mice (P < 0.05). An acute hypoxic challenge decreased CBF (P < 0.05) in untrained VEGF , untrained VEGF and trained VEGF mice, but not trained VEGF mice. VEGF , but not VEGF , mice were able to acutely run on a treadmill at an intensity sufficient to increase hippocampus VEGF levels. These data suggest that VEGF expressed by skeletal myofibers may directly or indirectly regulate both hippocampal blood flow and neurogenesis.

Cigarette smoke directly impairs skeletal muscle function through capillary regression and altered myofibre calcium kinetics in mice

“…Figure C shows confocal images of a representative soleus fibre immunostained for muscle stem cell markers Pax7+ and Nestin‐GFP. Nestin is a marker for quiescent muscle stem cells (Rich et al . 2017).…”

“…Male C57BL/6J mice (10 weeks of age) were housed three to four per cage in a pathogen‐free vivarium, maintained on a 12 h:12 h day–night cycle and provided standard chow (Harlan Tekland 8604, Madison, WI, USA) and tap water ad libitum . Nestin‐green fluorescent protein (GFP) mice were generated and kindly provided by Dr M. Yamaguchi (Rich et al . 2017).…”

Exercise makes your brain bigger: skeletal muscle VEGF and hippocampal neurogenesis

“…Hippocampal blood flow was substantially lower in the myofibre VEGF‐null mice (Rich et al . ), although this did not appear to result from decreased angiogenesis in the dentate gyrus, since the number of new endothelial cells (defined as CD31+/BrdU+ cells) was similar in the two groups. However, it may indicate that adequate hippocampal blood flow is a necessary prerequisite for neurogenesis.…”

“…In agreement with this, Rich et al . () also found that the VEGF gene‐ablated mice were unable to improve their exercise performance, despite performing a similar voluntary training regime to their normal littermates.…”

“…In their study in the current issue of The Journal of Physiology , Rich et al . () investigated whether VEGF released by skeletal myofibres contributed to exercise‐induced hippocampal proliferation: the group compared the effects of exercise training between adult conditional skeletal‐myofibre‐specific VEGF gene‐ablated mice (VEGF HSA−/− ) and non‐ablated (VEGF f/f ) littermates.…”