Galectin-3 andN-acetylglucosamine promote myogenesis and improve skeletal muscle function in themdxmodel of Duchenne muscular dystrophy

Abstract

The muscle membrane, sarcolemma, must be firmly attached to the basal lamina. The failure of proper attachment results in muscle injury, which is the underlying cause of Duchenne muscular dystrophy (DMD), where mutations in the dystrophin gene disrupts the firm adhesion. In DMD patients, even moderate contraction causes damage, leading to progressive muscle degeneration. The damaged muscles are repaired through myogenesis. Consequently, myogenesis is highly active in DMD patients, and the repeated activation of myogenesis leads to the exhaustion of the myogenic stem cells. Therefore, approaches to reducing the risk of the exhaustion are to develop a treatment that strengthens the interaction between the sarcolemma and the basal lamina, and increases the efficiency of myogenesis. Galectin-3 is an oligosaccharide-binding protein and known to be involved in cell-cell interactions and cell-matrix interactions. Galectin-3 is expressed in myoblasts and skeletal muscle while its function in muscle remains elusive. In this study, we found evidence that galectin-3 and the monosaccharide N-acetylglucosamine, which increases the ligands (oligosaccharides) of galectin-3, promotes myogenesis in vitro. Moreover, in the mdx mouse model of DMD, treatment with N-acetylglucosamine increased the muscle force production. Our results demonstrate that treatment with N-acetylglucosamine can mitigate the burden of DMD.

Integrated glycoproteomics identifies a role ofN-glycosylation and galectin-1 on myogenesis and muscle development

“…Administration of recombinant galectin-1 to the mdx mouse model of muscle dystrophy increased utrophin and integrin expression, and improved skeletal muscle function(14). Furthermore, enhanced muscle function has also been observed with exogenous galectin-3 expression in a similar mdx mouse model(65). Our data further support these observations revealing overexpression of galectin-1 increases muscle mass during postnatal muscle development in mice.…”

Integrated Glycoproteomics Identifies a Role of N-Glycosylation and Galectin-1 on Myogenesis and Muscle Development

“…Administration of recombinant galectin-1 to the mdx mouse model of muscle dystrophy increased utrophin and integrin expression, and improved skeletal muscle function (14). Furthermore, enhanced muscle function has also been observed with exogenous galectin-3 expression in a similar mdx mouse model (66). Our data further support these observations revealing overexpression of galectin- Therefore, galectins have been primarily studied in the context of extracellular lattice formation however, there is growing evidence to suggest galectins may regulate intracellular signaling via lysosomal trafficking (70).…”

First clinical and myopathological description of a myofibrillar myopathy with congenital onset and homozygous mutation in FLNC

“…Given that our proteomic profiling approach focused on potential changes of protein signature in the entire muscle upon expression of mutant FLNC, we next confirmed the altered abundances of galectin‐3 and transketolase. Hereby, galectin‐3 was selected as it is known to promote myogenesis (Rancourt et al, 2018) and transketolase (involved in sugar metabolism) based on the fact that FLNC is known to be involved in regulation of metabolic processes (Furst et al, 2013; Leber et al, 2016; Molt et al, 2014). These studies revealed a (sub)sarcolemmal increase of galectin‐3 in both, the recessive and the dominant case (white arrows in Figure 4c).…”

“…Given that a variety of myosin‐ or myosin‐modulating proteins are known to be predominantly expressed in certain fiber types, a vulnerability of those—as identified by our proteomic profiling—most likely suggests a predominance of type 1 fibers (a finding observed in a variety of congenital myopathies). Increased expression of galectin‐3 as a known promoter of myogenesis improving skeletal muscle function in mdx mice (mouse model of Duchenne muscular dystrophy; DMD; Rancourt et al, 2018) suggests activation of myocellular compensatory mechanisms. However, the progressive nature of the muscle disease in our patient with current loss of ambulation, might accord with the assumption that the pathological cascades triggered by the lesions and concomitant protein aggregate formation not only significantly contributed to muscle cell vulnerability but also led to apoptosis.…”