Activation of GPR30 improves exercise capacity and skeletal muscle strength in senescent female Fischer344 × Brown Norway rats

Abstract

The molecular mechanisms of muscle weakness and sarcopenia in postmenopausal women are largely unknown. To determine the effect of a new estrogen receptor, GPR30, in the maintenance of exercise capacity and skeletal muscle function in females, the selective GPR30 agonist, G1 (100 μg/kg/day), or vehicle (V, soybean oil) was administered subcutaneously daily (n=7 per group) to ovariectomized (OVX) 27-month-old Fischer 344×Brown Norway (F344BN) female rats. Following 8 weeks of treatment, the exercise capacity (treadmill walk time to exhaustion) was reduced in OVX vs. sham rats (5.1±1.4 vs. 11.0±0.9 min, P<0.05), and chronic G1 restored exercise capacity (12.9±1.2 min; P<0.05 vs. OVX-V). Similarly, the peak twitch of electrically stimulated soleus muscles was decreased by 22% in OVX vs. sham rats (P<0.05), and G1 attenuated this decline (P<0.05). Western blot analysis showed that chronic G1 treatment attenuated OVX-associated decreases in heat shock protein (HSP) 90, HSP70, and HSP27 expressions. In vitro studies using the L6 myoblast cell line demonstrated that G1 increased mRNA levels of HSPs in cultured cells. Collectively, these data demonstrate that the activation of GPR30 mitigates the adverse effects of estrogen loss on exercise capacity and skeletal muscle contractile function in old F344BN rats. The protective effects of GPR30 might be through its upregulation of heat shock proteins in skeletal muscle.

(-)-Epicatechin stimulates mitochondrial biogenesis and cell growth in C2C12 myotubes via the G-protein coupled estrogen receptor

“…Although the exact mechanism linked to (−)-EPI effects on MiB is not fully understood, there is indirect evidence for a possible role mediated by GPER (Moreno-Ulloa et al, 2015a). GPER activation by selective ligands has been shown to trigger MiB in vitro and in vivo (Sbert-Roig et al, 2016) and can enhance SkM function in vivo (Wang et al, 2016). Results generated in this study suggest that: (i) (−)-EPI, at physiologically relevant concentrations, increases the length and width of C2C12 myotubes; (ii) (−)-EPI stimulates MiB as per increases in endpoints linked to mitochondrial structure and biogenesis; (iii) GPER is involved in the stimulation of MiB and myotube growth by (−)-EPI treatment and; (iv) (−)-EPI induces a higher response than G-1 in stimulating MiB and myotube growth when both ligands are compared at concentrations eliciting their individual maximal attainable effect.…”

“…GPER is a transmembrane receptor that binds its physiological ligand 17β-estradiol (agonist) (Revankar et al, 2005) and synthetic ones including G-1 (agonist) (Bologa et al, 2006) and G-36 (antagonist) (Dennis et al, 2011). In SkM, GPER activation has been shown to improve exercise capacity and SkM strength (Wang et al, 2016). Thus, based on evidence suggesting increases on MiB in SkM cells by either (−)-EPI treatment or GPER activation as well as on our endothelial cell data, we hypothesized that GPER is (at least in part) involved in mediating the effects of (−)-EPI on MiB in muscle cells.…”

Activation of GPER ameliorates experimental pulmonary hypertension in male rats

“…We recently reported that MCT-treated rats developed progressive exercise intolerance (Alencar et al, 2014). Recently, it was found that GPER activation by G1 reduced skeletal muscle dysfunction and exercise intolerance in rats with LV diastolic dysfunction (Wang et al, 2016). Here, we showed that the reduced exercise performance, defined by the time to exhaustion on the treadmill, 28 days after MCT application, was significantly correlated with alterations in PAT, RVSP, and LV cardiac output.…”

Aging of the musculoskeletal system: How the loss of estrogen impacts muscle strength

“…The few rodent studies that have been conducted show that estrogen treatment to males or ovariectomized females attenuates exercise-induced HSP70 and HSP72 (official name HspA1A) response and has no effect on HSP27 in hindlimb muscles [63,[71][72][73]. Wang and coworkers further showed that loss of estrogen in female rats blunted basal protein levels of HSP70, HSP27, and HSP90 in skeletal muscle [74]. Thus, it is unclear how and which HSPs are regulated by estrogen; however, these studies provide impetus for future research investigating estrogen's role in its protection against apoptosis through HSP modulation especially in the complex in vivo environment of skeletal muscle.…”