CD44 contributes to hyaluronan-mediated insulin resistance in skeletal muscle of high-fat-fed C57BL/6 mice

Abstract

Extracellular matrix hyaluronan is increased in skeletal muscle of high-fat-fed insulin-resistant mice, and reduction of hyaluronan by PEGPH20 hyaluronidase ameliorates diet-induced insulin resistance (IR). CD44, the main hyaluronan receptor, is positively correlated with type 2 diabetes. This study determines the role of CD44 in skeletal muscle IR. Global CD44-deficient ( cd44−/−) mice and wild-type littermates ( cd44+/+) were fed a chow diet or 60% high-fat diet for 16 wk. High-fat-fed cd44−/− mice were also treated with PEGPH20 to evaluate its CD44-dependent action. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp (ICv). High-fat feeding increased muscle CD44 protein expression. In the absence of differences in body weight and composition, despite lower clamp insulin during ICv, the cd44−/− mice had sustained glucose infusion rate (GIR) regardless of diet. High-fat diet-induced muscle IR as evidenced by decreased muscle glucose uptake (Rg) was exhibited in cd44+/+ mice but absent in cd44−/− mice. Moreover, gastrocnemius Rg remained unchanged between genotypes on chow diet but was increased in high-fat-fed cd44−/− compared with cd44+/+ when normalized to clamp insulin concentrations. Ameliorated muscle IR in high-fat-fed cd44−/− mice was associated with increased vascularization. In contrast to previously observed increases in wild-type mice, PEGPH20 treatment in high-fat-fed cd44−/− mice did not change GIR or muscle Rg during ICv, suggesting a CD44-dependent action. In conclusion, genetic CD44 deletion improves muscle IR, and the beneficial effects of PEGPH20 are CD44-dependent. These results suggest a critical role of CD44 in promoting hyaluronan-mediated muscle IR, therefore representing a potential therapeutic target for diabetes.

Alterations in protein translation and carboxylic acid catabolic processes in diabetic kidney disease

“…CD44 acts as both a receptor for hyaluronan and osteopontin, of which both molecules are associated with the pathogenesis of DM. For example, hyaluronan promotes muscle insulin resistance (38). There is also a critical role for osteopontin in DKD.…”

Collagen 24 α1 Is Increased in Insulin-Resistant Skeletal Muscle and Adipose Tissue

“…The ECM is composed of the interstitial matrix (e.g., fibrillar collagens, fibronectin, hyaluronan) and the basement membrane (e.g., collagen IV and laminin), which provide the structural support for tissues and are required for cell adhesion and migration during growth, differentiation, morphogenesis and wound healing [3]. Increased deposition of various ECM components (e.g., collagens, hyaluronan and osteopontin) and their binding to the ECM receptors (e.g., integrins and CD44) have been linked to the development of obesity-associated insulin resistance in skeletal muscle [4][5][6], adipose tissue [7,8] and the liver [9].…”

“…Collagens are the most abundant components of the ECM, consisting of three α-helical chains made of the repetitious amino acid sequence glycine-X-Y, where X and Y are frequently proline or hydroxyproline. It was previously shown that collagen isoforms I (1), III (3), IV (4), V (5), VI (6) and XVIII (18) were increased in insulin-resistant tissues [1,14]. Collagen XXIV (24) was discovered as a new member of the fibril-forming family of collagen molecules and has been demonstrated to be crucial for osteoblastic differentiation and mineralisation [15,16].…”

Integrative analysis prioritizes the relevant genes and risk factors for chronic venous disease

“…Although there is still a lack of direct evidence, the current outcomes have suggested the possible roles of prioritized genes in CVD progression. The prioritized genes such as RSPO3, TUFM, SBF2, TBCE, PIEZO1, CD44, ABCB10, C1S, HDAC7, and ATF-1 have also been associated with the potential causative risk factors identified by our MR analysis [63][64][65][66][67][68][69][70][71][72] . These genes linking risk factors to CVD should be targets in future studies of the molecular basis of possible genetic contributions to CVD.…”