Alcohol Differentially Alters Extracellular Matrix and Adhesion Molecule Expression in Skeletal Muscle and Heart

Abstract

Background The production of fibrosis in response to chronic alcohol abuse is well recognized in liver but has not been fully characterized in striated muscle and may contribute to functional impairment. Therefore, the purpose of this study was to use an unbiased discovery-based approach to determine the effect of chronic alcohol consumption on the expression profile of genes important for cell-cell and cell-extracellular matrix (ECM) interactions in both skeletal and cardiac muscle. Methods Adult male rats were pair-fed an alcohol-containing liquid diet or control diet for 24 wks, and skeletal muscle (gastrocnemius) and heart collected in the freely fed state. A pathway-focused gene expression PCR array was performed on these tissues to assess mRNA content for 84 ECM proteins, and selected proteins were confirmed by Western analysis. Results In gastrocnemius, alcohol feeding up-regulated expression of 11 genes and down-regulated expression of 1 gene. Alcohol increased fibrosis as indicated by increased mRNA and/or protein for collagen α1(I), α2(I), α1(III) and α2(IV) as well as hydroxyproline. Alcohol also increased α-smooth muscle actin protein, an index of myofibroblast activation, but no concomitant change in TGF-β was detected. The mRNA and protein content for other ECM components, such as integrin α-5, L-selectin, PECAM, Sparc and Adamts2 was also increased by alcohol. Only laminin α-3 mRNA was decreased in gastrocnemius from alcohol-fed rats, while 66 ECM- or cell adhesion-related mRNAs were unchanged by alcohol. For heart, expression of 16 genes was up-regulated, expression of 3 genes was down-regulated, and 65 mRNAs were unchanged by alcohol; there were no common alcohol-induced gene expression changes between heart and skeletal muscle. Finally, alcohol increased TNFα and IL-12 mRNA in both skeletal and cardiac muscle, but IL-6 mRNA was increased and IL-10 mRNA decreased only in skeletal muscle. Conclusions These data demonstrate a fibrotic response in striated muscle from chronic alcohol-fed rats which is tissue-specific in nature, suggesting different regulatory mechanisms.

Cardiac Toxicity From Ethanol Exposure in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

“…Similarly, MMP9 concentrations are significantly higher in human sera of chronic alcohol abusers (Sillanaukee et al, 2002), and MMP9 mRNA and protein levels are increased in the myocardium of rats following acute ethanol exposure (Li et al, 2012). Collagen content in myocardium is approximately 10-fold higher in patients with alcoholic dilated cardiomyopathy than in controls without heart disease (Soufen et al, 2008), and collagen mRNA and/or protein expression in the heart are significantly increased in rats following long-term exposure to alcohol (El Hajj et al, 2014;Steiner et al, 2015).…”

Alcohol Vapor Inhalation as a Model of Alcohol‐Induced Organ Disease

“…Previous studies in our laboratory have shown that CIEV for 2 weeks increased LV collagen expression, which was associated with an altered matrix‐metalloproteinase (MMP) to tissue inhibitor of MMPs ratio favoring profibrotic signaling (El Hajj et al., ). Chronic alcohol diets have been shown to decrease cardiac mass, wall thickness, and function (Lang and Korzick, ; Steiner et al., ). Consistent with these studies, we found that CIEV decreased LV mass and wall thickness, increased heart rate, and increased systolic blood pressure.…”

Alcoholic Liver Disease on the Rise: Interorgan Cross Talk Driving Liver Injury

“…Impaired protein synthesis due to reduced mTORC1 signaling has been identified and consistently, autophagy is increased (Thapaliya et al, 2014). Unlike those in the liver, there have been few studies on skeletal muscle fibrosis and Lang's group in Hershey has performed seminal work in this area using a complementary genetic and functional approach to show that ethanol has a context specific effect on tissue fibrosis in the heart and skeletal muscle (Steiner et al, 2015). An increase in muscle profibrotic genes and collagen have the potential to adversely affect both the metabolic and contractile function with consequent impaired functional activity.…”