Impaired Cathepsin L Gene Expression in Skeletal Muscle Is Associated With Type 2 Diabetes

Abstract

To identify abnormally expressed genes associated with muscle insulin resistance or type 2 diabetes, we screened the mRNA populations using cDNA differential display combined with relative RT-PCR analysis from muscle biopsies of diabetes-prone C57BL/6J and diabetes-resistant NMRI mice fed with a high-fat or normal diet for 3 or 15 months. Six abnormally expressed genes were isolated from the mice after a 3-month fat feeding; one of them was cathepsin L. No significant difference in mRNA levels of these genes was observed between fatand normal-diet conditions in either strains. However, cathepsin L mRNA levels in muscle were higher in normal diet-fed C57BL/6J mice compared with normal diet-fed NMRI mice at 3 months (0.72 ؎ 0.04 vs. 0.51 ؎ 0.04 relative units, P < 0.01, n ‫؍‬ 8 -10) and at 15 months (0.41 ؎ 0.05 vs. 0.27 ؎ 0.04 relative units, P ‫؍‬ 0.01, n ‫؍‬ 9 -10). Further, cathepsin L mRNA levels in muscle correlated inversely with plasma glucose in both strains regardless of diets at 3 (r ‫؍‬ ؊0.49, P < 0.01, n ‫؍‬ 31) and 15 (r ‫؍‬ ؊0.42, P ‫؍‬ 0.007, n ‫؍‬ 39) months. To study whether cathepsin L plays a role in human diabetes, we measured cathepsin L mRNA levels in muscle biopsies taken before and after an insulin clamp from 12 monozygotic twin pairs discordant for type 2 diabetes and from 12 control subjects. Basal cathepsin L mRNA levels were not significantly different between the study groups. Insulin infusion increased cathepsin L mRNA levels in control subjects from 1.03 ؎ 0.30 to 1.90 ؎ 0.32 relative units (P ‫؍‬ 0.03). Postclamp cathepsin L mRNA levels were lower in diabetic twins but similar in nondiabetic twins compared with control subjects (0.66 ؎ 0.22, 1.16 ؎ 0.18 vs. 1.38 ؎ 0.21 relative units, P < 0.02, NS, respectively). Further, postclamp cathepsin L mRNA levels were correlated with insulin-mediated glucose uptake (r ‫؍‬ 0.37, P ‫؍‬ 0.03), particularly, with glucose oxidation (r ‫؍‬ 0.37, P ‫؍‬ 0.03), and fasting glucose concentrations (r ‫؍‬ ؊0.45, P < 0.01) across all three study groups. In conclusion, muscle cathepsin L gene expression is increased in diabetes-prone mice and related to glucose tolerance. In humans, insulin-stimulated cathepsin L expression in skeletal muscle is impaired in diabetic but not in nondiabetic monozygotic twins, suggesting that the changes may be secondary to impaired glucose metabolism. Diabetes 52:2411-2418, 2003 I nsulin resistance can be induced by high-fat intake in animals and humans (1-4) and is seen at the levels of whole-body and skeletal muscle (4,5). The degree of fat-induced insulin resistance varies according to different genetic backgrounds in humans (6) and in experimental animals (7-10). The C57BL/6J mouse is genetically prone to develop insulin resistance and diabetes. When challenged with a high-fat diet, the C57BL/6J mouse shows elevated plasma insulin and glucose levels compared with a control mouse strain (8,10). Therefore, strain-specific and fat-responsive genes could contribute to insulin resistance and glucose intolerance in C57BL/6J...

Proteases in cardiometabolic diseases: Pathophysiology, molecular mechanisms and clinical applications

“…In the skeletal muscle of diabetic subjects, reduced insulin-stimulated cathepsin L gene expression was also reported in this paper, suggesting that impaired cathepsin L expression is secondary to impaired glucose metabolism [214]. Cathepsin S levels strongly correlate with insulin resistance as reported by Jobs and coworkers, who in their study showed that subjects with higher cathepsin S levels had decreased insulin sensitivity and higher risk to develop type 2 diabetes [215].…”

“…Expression levels of cathepsin L in the muscle has been shown to be elevated in glucose intolerant mice [214]. In the skeletal muscle of diabetic subjects, reduced insulin-stimulated cathepsin L gene expression was also reported in this paper, suggesting that impaired cathepsin L expression is secondary to impaired glucose metabolism [214].…”

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