Effects of metformin on congenital muscular dystrophy type 1A disease progression in mice: a gender impact study

Abstract

Congenital muscular dystrophy with laminin α2 chain-deficiency (LAMA2-CMD) is a severe muscle disorder with complex underlying pathogenesis. We have previously employed profiling techniques to elucidate molecular patterns and demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models. Thus, we hypothesize that skeletal muscle metabolism may be a promising pharmacological target to improve muscle function in LAMA2-CMD. Here, we have investigated whether the multifunctional medication metformin could be used to reduce disease in the dy2J/dy2J mouse model of LAMA2-CMD. First, we show gender disparity for several pathological hallmarks of LAMA2-CMD. Second, we demonstrate that metformin treatment significantly increases weight gain and energy efficiency, enhances muscle function and improves skeletal muscle histology in female dy2J/dy2J mice (and to a lesser extent in dy2J/dy2J males). Thus, our current data suggest that metformin may be a potential future supportive treatment that improves many of the pathological characteristics of LAMA2-CMD.

Antioxidants Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy

“…As previously described, we observed a decrease in dy 2J /dy 2J forelimb grip strength at six weeks of age [25,32] (Figure 2A,C). Notably, NAC treatment significantly prevented grip strength reduction in dy 2J /dy 2J mice (Figure 2A).…”

“…Several other compounds already approved for human use have been evaluated in different mouse models of LAMA2-CMD and include for example omigapil (tested in dy W /dy W and dy 2J /dy 2J mice) [56]; doxicycline (tested in dy W /dy W ) [57]; bortezomib (tested in dy 3K /dy 3K and dy 2J /dy 2J ) [22,35]; losartan and a losartan-derivative (tested in dy W /dy W and dy 2J /dy 2J ) [58][59][60]; metformin (tested in dy 2J /dy 2J ) [25], prednisolone (tested in dy/dy) [61] and clenbuterol (tested in dy/dy) [62]. It should be noted that these drugs only partially ameliorate disease (although it is incredibly difficult to compare studies that were performed in different mouse models, in different laboratories and with different outcome measures).…”

“…The relative amount of all mRNAs was calculated using the comparative CT method (∆∆Ct). Rplp0 was used as the invariant control[25].…”

A Family of Laminin α2 Chain-Deficient Mouse Mutants: Advancing the Research on LAMA2-CMD

“…Although the majority of dystrophic features are similar between dy 2J /dy 2J males and females (dystrophic features in different muscle types) (Pasteuning-Vuhman et al, 2018), one has to take into consideration that gender-related phenotype differences (weight gain, creatine kinase levels (CK), water intake, muscle strength), exist in this mouse model (Fontes-Oliveira et al, 2018;Moreira Soares Oliveira et al, 2018;Pasteuning-Vuhman et al, 2018), which thus far has not been demonstrated for other LAMA2-CMD mutants. While these differences do not impact the overall disease presentation (they are rather subtle and a more severe phenotype cannot be attributed to any gender), they could significantly influence the outcomes of therapeutic strategies (Fontes-Oliveira et al, 2018). Hence, analysis of the treatment effects in dy 2J /dy 2J mice should take into account both genders separately.…”

“…One week later, other dystrophic hallmarks (central nucleation, decreased muscle strength) are established and fully developed pathology can be observed at 6-8 weeks of age, including increased production of several extracellular matrix components, muscle atrophy and decreased body weights in both genders (Nevo et al, 2010;McKee et al, 2017;Fontes-Oliveira et al, 2018;Moreira Soares Oliveira et al, 2018; Tables 2, 3). Reduced muscle strength and mobility between 4-10 weeks of age has been clearly documented in several studies (Dadush et al, 2010;McKee et al, 2017;Fontes-Oliveira et al, 2018;Gawlik et al, 2018;Moreira Soares Oliveira et al, 2018;Pasteuning-Vuhman et al, 2018). The follow-up of the dy 2J /dy 2J mouse condition up to 34 weeks of age did not reveal significant muscle pathology progression compared to 6week-old mice (Pasteuning-Vuhman et al, 2018), except for the additional body weight loss between week 6-10 (Fontes- Oliveira et al, 2018).…”