Exercise mitigates the effects of hyperhomocysteinemia on adverse muscle remodeling

Abstract

Hyperhomocysteinemia (HHcy) is known for causing inflammation and vascular remodeling, particularly through production of reactive oxygen species (ROS) and matrix metalloproteinase‐9 (MMP‐9) activation. Although its effect on the skeletal muscle is unclear, HHcy can cause skeletal muscle weakness and functional impairment by induction of inflammatory mediators and macrophage mediated injury. Exercise has been shown to reduce homocysteine levels and therefore, could serve as a promising intervention for HHcy. The purpose of this study was to investigate whether HHcy causes skeletal muscle fibrosis through induction of inflammation and determine whether exercise can mitigate these effects. C57BL/6J (WT) and CBS+/− (HHcy) mice were administered a 6 weeks treadmill exercise protocol. Hindlimb perfusion was measured via laser Doppler. Measurement of skeletal muscle protein expression was done by western blot. Levels of skeletal muscle MMP‐9 mRNA were determined by qPCR. Collagen deposition in the skeletal muscle was measured using Masson's trichrome staining. In CBS+/− mice, HHcy manifested with decreased body weight and femoral artery lumen diameter, as well as a trend of lower hindlimb perfusion. These mice displayed increased wall to lumen ratio, mean arterial blood pressure, collagen deposition, and elevated myostatin protein expression. Exercise mitigated the effects above in CBS+/− mice. Skeletal muscle from CBS+/− mice had elevated markers of remodeling and hypoxia: iNOS, EMMPRIN, and MMP‐9. We conclude that HHcy causes skeletal muscle fibrosis possibly through induction of EMMPRIN/MMP‐9 and exercise is capable of mitigating the pathologies associated with HHcy.

Hydrogen sulphide mitigates homocysteine-induced apoptosis and matrix remodelling in mesangial cells through Akt/FOXO1 signalling cascade

“…We and others have shown that Hcy induces oxidative stress, which in turn induces MMPs in a variety of pathological conditions, both in vivo and in vitro settings [32,46,47]. Changes in MMPs expression and activity can lead to disproportional ECM synthesis and accumulation causing deleterious vascular remodelling [48,49].…”

Hydrogen sulfide improves postischemic neoangiogenesis in the hind limb of cystathionine-β-synthase mutant mice via PPAR-γ/VEGF axis

“…CBS is one of the key enzymes in the transsulfuration pathway, and heterozygous CBS deficiency (CBS+/À) has proved to be a useful model for analyzing the effects of mild to a severe endogenous elevation in the levels of Hcy (Familtseva et al 2014;Nandi and Mishra 2017;Narayanan et al 2013;Tyagi et al 2011Tyagi et al , 2012Watanabe et al 1995;Winchester et al 2018;Yang et al 2018). Hence, in this study, we used CBS +/À mouse model to dissect the effect(s) of HHcy on neoangiogenesis in the skeletal muscle and evaluate whether exogenous administration of GYY4137 (an H 2 S donor) could improve this effect(s).…”

Restoration of skeletal muscle homeostasis by hydrogen sulfide during hyperhomocysteinemia-mediated oxidative/ER stress condition

“…HHcy is a known risk factor for vascular diseases (Ganguly and Alam 2015), however several studies also reported that HHcy leads to skeletal muscle weakness and functional impairment (Kalra et al 1985; Kanwar et al 1976; Veeranki et al 2014, 2015; Veeranki and Tyagi 2013, 2015a; Winchester et al 2018). Children born with severe homocystinuria due to CBS deficiency exhibit reduced body weight, skeletal muscle myopathy, and die in teenage years (Majumder et al 2017).…”

“…Children born with severe homocystinuria due to CBS deficiency exhibit reduced body weight, skeletal muscle myopathy, and die in teenage years (Majumder et al 2017). A clinical manifestation of HHcy displays decreased body mass and loss of skeletal muscle mass, which ultimately lead to myopathy (Kalra et al 1985; Kanwar et al 1976; Veeranki et al 2014; 2015; Veeranki and Tyagi 2013, 2015a; Winchester et al 2018). Results from our laboratory previously showed that HHcy mice (CBS +/− gene) have lower body mass and less fatigue resistance and produce less contractile force, have lower muscle ATP levels, low dystrophin, and mitochondrial transcription factor A (mtTFA) compared to control mice (C57BL/6J) (Veeranki and Tyagi 2015a).…”

“…Patients with CBS gene mutation lead to dysfunction in endogenous H 2 S biosynthesis (Beard and Bearden 2011), suggesting that these patients are more prone to oxidative stress-mediated damages due to malfunction in Hcy metabolism and inefficient H 2 S biosynthesis (Szabó 2007). CBS is a crucial enzyme in the transsulfuration pathway, and heterozygous CBS deficient (CBS +/− ) has proved a useful model for HHcy, which shows mild to a severe endogenous elevation of Hcy in several tissues in mice (Familtseva et al 2014; Nandi and Mishra 2017; Narayanan et al 2013; Tyagi et al 2011, 2012; Watanabe et al 1995; Winchester et al 2018; Yang et al 2018). Studies have been performed using the CBS model to show that these mice have less H 2 S levels in their blood and showed oxidative stress-mediated damages (Ishihara et al 2008; John et al 2017).…”