Cross-sectional study into age-related pathology of mouse models for limb girdle muscular dystrophy types 2D and 2F

Abstract

Limb girdle muscular dystrophy (LGMD) types 2D and 2F are caused by mutations in the genes encoding for α- and δ-sarcoglycan, respectively, leading to progressive muscle weakness. Mouse models exist for LGMD2D ( Sgca -/- ) and 2F ( Sgcd -/- ). In a previous natural history study, we described the pathology in these mice at 34 weeks of age. However, the development of muscle pathology at younger ages has not been fully characterised yet. We therefore performed a study into age-related changes in muscle function and pathology by examining mice at different ages. From 4 weeks of age onwards, male mice were subjected to functional tests and sacrificed at respectively 8, 16 or 24 weeks of age. Muscle histopathology and expression of genes involved in muscle pathology were analysed for several skeletal muscles, while miRNA levels were assessed in serum. In addition, for Sgcd -/- mice heart pathology was assessed. Muscle function showed a gradual decline in both Sgca -/- and Sgcd -/- mice. Respiratory function was also impaired at all examined timepoints. Already at 8 weeks of age, muscle pathology was prominent, and fibrotic, inflammatory and regenerative markers were elevated, which remained relatively constant with age. In addition, Sgcd -/- mice showed signs of cardiomyopathy from 16 weeks of age onwards. These results indicate that Sgca -/- and Sgcd -/- are relevant disease models for LGMD2D and 2F.

Selective ablation of Nfix in Macrophages preserves Muscular Dystrophy by inhibiting FAPs-dependent fibrosis

“…Particularly, they develop calcification within skeletal muscle 61 , while in Sgca null mice calcification represents less than 1% of gastrocnemius, quadriceps, triceps, or DIA area 29 . The formation of heterotopic ossification seems to be linked to the total absence of dystrophin expression 62 , indeed in Sgca null mice, α-sarcoglycan is absent but, even if reduced, dystrophin is still present in dystrophic muscles 30 .…”

“…To understand in which proportion the rescue of dystrophic phenotype observed was due to the lack of Nfix in MPs, we generated Sgca null dystrophic mice deleted for Nfix in MPs: the LysM CRE :Nfix fl/fl :sgca (-/-) mice (hereafter named ΦNfix (-/-) :α (-/-) ). We decided to use the Sgca null mice because its phenotype is more severe compared to the mdx mice and better recapitulates the progression of DMD patients 4,[29][30][31] . The LysM CRE :Nfix fl/fl :sgca (+/-) (hereafter named ΦNfix (-/-) :α (+/-) ) mouse was used as nondystrophic control and the Nfix fl/fl :sgca (-/-) mice (hereafter named Nfix fl/fl :α (-/-) ) as dystrophic control.…”

“…We also looked at the Dia histology because this muscle better reflects the dystrophic phenotype 29,32 . As for the TA, normal muscle histology was observed in the ΦNfix (-/-) :α (+/-) mice (Figure 4a).…”

Improving translatability of preclinical studies for neuromuscular disorders: lessons from the TREAT-NMD Advisory Committee for Therapeutics (TACT)

“…The choice of readouts and biomarkers needs to be tailored to the drug tested and to the expected efficacy, both on the molecular level and for functional, clinically relevant aspects. Notably, as in human trials, preclinical studies can only be properly planned when the natural history of the model system is known (see for example Gordish-Dressman et al, 2018;van Putten et al, 2019;Verhaart et al, 2019), as this will also guide researchers in determining when to start the intervention and when and how to assess its therapeutic effects.…”

Impact of oxidative posttranslational modifications of SERCA2 on heart failure exacerbation in young patients with non-ischemic cardiomyopathy: A pilot study

“…A positively stained area for each primary antibody was quantified using BZ-X analyzer software (Keyence, Osaka, JPN). Percentages of the positively stained area by each antibody were calculated as (%) = (positively stained area)/(entire EMB tissue area), and these values were used as indices of protein expression [24], [25], [26]. OPTM of SERCA2 was determined by (S-SERCA2%)/(SERCA2%), (N-SERCA2%)/(SERCA2%), or (S-SERCA2% + N-SERCA2%)/(SERCA2%).…”