Abstract
Laminopathies are a family of monogenic multi-system diseases resulting from mutations in the LMNA gene which include a wide range of neuromuscular disorders. Although lamins are expressed in most types of differentiated cells, LMNA mutations selectively affect only specific tissues by mechanisms that remain largely unknown. We have employed the combination of functional in vitro experiments and transcriptome analysis in order to determine how two LMNA mutations associated with different phenotypes affect skeletal muscle development and metabolism. We used a muscle differentiation model based on C2C12 mouse myoblasts genetically modified with lentivirus constructs bearing wild-type human LMNA (WT-LMNA) or R482L-LMNA/G232E-LMNA mutations, linked to familial partial lipodystrophy of the Dunnigan type and muscular dystrophy phenotype accordingly. We have shown that both G232E/R482L-LMNA mutations cause dysregulation in coordination of pathways that control cell cycle dynamics and muscle differentiation. We have also found that R482/G232E-LMNA mutations induce mitochondrial uncoupling and a decrease in glycolytic activity in differentiated myotubes. Both types of alterations may contribute to mutation-induced muscle tissue pathology.
Highlights
Laminopathies are the family of monogenic multi-system disorders that result from mutations in the LMNA gene, which encodes for nuclear lamins A and C
We further proved the ability of all transducted myoblasts successfully differentiate into myotubes (Figure 1B) and demonstrated that hLMNA mRNA expression levels increased significantly in differentiated myotubes compared to non-differentiated myoblasts as expected (Figure 1C) [42]
We have shown here that both G232E-LMNA and R482L-LMNA mutations induce global disruptions in the coordination of myogenesis: these mutations induce the decrease to proliferate and stimulate spontaneous activation of a pro-myogenic program in proliferating C2C12 mouse myoblasts, and cause the delay in cell cycle suppression after myogenesis stimulation, which results in disturbed coordination of late steps of myocyte differentiation
Summary
Laminopathies are the family of monogenic multi-system disorders that result from mutations in the LMNA gene, which encodes for nuclear lamins A and C. Lamins are expressed in most differentiated tissues, particular LMNA mutations selectively affect only specific tissues by mechanisms that remain largely unknown. Genotype–phenotype association studies have raised the hypotheses that different laminopathies selectively affect specific tissues through the ability of nuclear lamina to influence the chromatin status under differentiation and mechanical stress in a. LMNA mutations may impact the function of the nuclear envelope as a signaling platform, affecting the dynamics of epigenomic perturbations and gene expression in regenerating skeletal muscle [14,15]. Duchenne Muscular Dystrophy (DMD) is characterized by global metabolic alterations: myocytes of DMD patients and mdx mice (mdx mice possess a spontaneous point mutation in exon 23 of dystrophin that prevents expression of full-length dystrophin; the model is used for studying DMD) exhibit reduced oxygen consumption, spare capacity, and mitochondrial complex I activity [16]. Primary cells form patients with lamin-associated lipodystrophy and corresponding animal models reveal metabolic alterations, providing evidence for the role of lamin A/C in regulating cell metabolism [19]
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