The impact of skeletal muscle contraction on CD146⁺Lin⁻ pericytes

Abstract

Unaccustomed resistance exercise can initiate skeletal muscle remodeling and adaptive mechanisms that can confer protection from damage and enhanced strength with subsequent stimulation. The myofiber may provide the primary origin for adaptation, yet multiple mononuclear cell types within the surrounding connective tissue may also contribute. The purpose of this study was to evaluate the acute response of muscle-resident interstitial cells to contraction initiated by electrical stimulation (e-stim) and subsequently determine the contribution of pericytes to remodeling as a result of training. Mice were subjected to bilateral e-stim or sham treatment. Following a single session of e-stim, NG2+CD45−CD31− (NG2+Lin−) pericyte, CD146+Lin− pericyte, and PDGFRα+ fibroadipogenic progenitor cell quantity and function were evaluated via multiplex flow cytometry and targeted quantitative PCR. Relative quantity was not significantly altered 24 h postcontraction, yet unique gene signatures were observed for each cell population at 3 h postcontraction. CD146+Lin− pericytes appeared to be most responsive to contraction, and upregulation of genes related to immunomodulation and extracellular matrix remodeling was observed via RNA sequencing. Intramuscular injection of CD146+Lin− pericytes did not significantly increase myofiber size yet enhanced ECM remodeling and angiogenesis in response to repeated bouts of e-stim for 4 wk. The results from this study provide the first evidence that CD146+Lin− pericytes are responsive to skeletal muscle contraction and may contribute to the beneficial outcomes associated with exercise.

Early time course of change in angiogenic proteins in human skeletal muscle and vascular cells with endurance training

“…Our baseline data from cells isolated before training revealed that the pericytes contained a number of angiogenic factors, known to be of importance for the regulation of capillary growth in skeletal muscle 24 . The levels of VEGF protein were similar in the pericytes and endothelial cells, whereas the levels of TSP‐1 and VEGFR2 were 6‐ and 10‐fold higher, respectively, in the endothelial cells than in pericytes, indicating that pericytes may have a paracrine pro‐angiogenic function, which supports previous evidence of a role in angiogenesis in skeletal muscle 17 , 18 , 30 , 35 , 36 , 37 Structurally, there is a close proximity between pericytes and endothelial cells with shared basement membrane 16 , 37 which would facilitate a directed release of VEGF from the pericyte to the endothelial cells, although direct evidence for such a mechanism is lacking. Somewhat unexpectedly, the pericytes did not express measurable levels of Tie2.…”

“…In general, content of angiogenic proteins have never been determined in isolated skeletal muscle‐derived endothelial cells and pericytes. Pericytes are of interest in this context as evidence is accumulating for their role in skeletal muscle angiogenesis 16‐18 . Moreover, it is feasible that the time course and relative magnitude of change in endothelial cells and pericytes differs from that in whole muscle.…”

Electrically stimulated hind limb muscle contractions increase adult hippocampal astrogliogenesis but not neurogenesis or behavioral performance in male C57BL/6J mice

“…E-stim mice were subjected to bilateral electrical stimulation of the sciatic nerve as previously described 21 . Prior to treatment, mice were anesthetized using isoflurane at a concentration of 2–5% during induction.…”

Distinct Fibroblast Lineages Give Rise to NG2+ Pericyte Populations in Mouse Skin Development and Repair

“…Pericytes have been shown to express a range of different markers, individually and in combination (Armulik et al, 2011;Hsu et al, 2019). The most commonly used include Rgs5 (Bondjers et al, 2003), Pdgfrβ (Armulik et al, 2011), Nestin (Birbrair et al, 2013a), Tbx18 , CD146 (Dvoretskiy et al, 2019), and Neural/glial antigen 2 (Ng2) (Armulik et al, 2011). However, none of these markers are pericyte specific as each marker can identify multiple dermal cell populations; for example Pdgfrβ is also expressed by adventitial fibroblasts (Stapor et al, 2014) and CD146 is also expressed by endothelial cells (Crisan et al, 2008;Guerrero-Juarez et al, 2019;Gay et al, 2020;Haensel et al, 2020).…”