LMNA rs4641 and the Muscle Lamin A and C Isoforms in Twins-Metabolic Implications and Transcriptional Regulation

Context: Lamins are essential for nuclear shape and function. Polymorphisms in LMNA may associate with fat and muscle development and aging. Objective: Our aim was to determine the influence of LMNA rs4641 on lean body mass (LBM) and fat mass (FM), in vivo metabolism, and expression of LMNA transcripts in human skeletal muscle. Design: We genotyped LMNA rs4641 in 196 Danish twins who were extensively phenotypically characterized. We measured mRNA levels of LMNA transcripts, lamin A and C, in basal and insulin-stimulated skeletal muscle biopsies. Results: The rs4641 T-allele was associated with increased weight and body mass index (P = 0.02), including increased FM (P = 0.03) and LBM (P = 0.004). Impact of rs4641 on FM was seen primarily among elderly twins. The T-allele was associated with elevated fasting plasma insulin levels (P = 0.01) and homeostasis model of insulin resistance (P = 0.02) in young twins. T-allele carriers did not exhibit consistent changes of first phase insulin secretion, nor did they exhibit significant peripheral or hepatic insulin resistance, and rs4641 did not influence muscle lamin A or C mRNA levels. The lamin A-to-C mRNA ratio was increased with acute insulin stimulation (P < 0.0005), and the lamin A and C mRNA levels were diminished in young compared to elderly twins (P < 0.001). Conclusions: The LMNA rs4641 T-allele is associated with increased LBM and FM with more fat relative to muscle in elderly twins, which may impact risk of type 2 diabetes. Increased mRNA levels of lamins with age may counteract muscle wasting, and influence of insulin on lamin A-to-C ratio suggests a role in cytoskeletal muscle protein regulation. (J Clin Endocrinol Metab 95: 3884-3892, 2010)