Distinct systemic metabolic features in limb-girdle muscular dystrophy type R1 mouse models as a potential early...

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• Limb-girdle muscular dystrophy type R1 (LGMDR1) stems from mutations in the CAPN3 gene, leading to progressive muscle weakness.
• Calpain-3 (CAPN3), a skeletal muscle protease, has both activity-dependent and -independent roles in cellular function.
• Previous studies used separate mouse models (knock-in and knockout) to investigate LGMDR1 pathology.

Purpose of the Study:

• To conduct a comprehensive, side-by-side analysis of knock-in (KI) and knockout (KO) mouse models of LGMDR1.
• To elucidate the functional roles of calpain-3 (CAPN3) in LGMDR1 pathogenesis.
• To understand the impact of CAPN3 deficiency on systemic energy metabolism and disease severity.

Main Methods:

• Long-term comparative analysis of CAPN3 KI and KO mice.
• Histochemical analysis to assess muscle pathology.
• Quantitative muscle proteomics and gene ontology analysis.
• Metabolomic analysis of skeletal muscle and liver tissues.

Main Results:

• Both KI and KO mice exhibited age-dependent LGMDR1 symptoms, with KO mice showing more severe pathology.
• Proteomic and gene ontology analyses revealed broader molecular changes in KO mice compared to KI mice.
• Skeletal muscle displayed an imbalanced branched-chain amino acid catabolic pathway, and liver showed reduced lipids and glycogen in KO mice, indicating systemic energy deficit.

Conclusions:

• Muscular dysfunction in LGMDR1 models is linked to compromised systemic energy balance.
• The severity of LGMDR1 pathology correlates with the extent of energy metabolism perturbation.
• Calpain-3 (CAPN3) plays a critical role in maintaining systemic energy homeostasis, beyond its direct proteolytic functions in muscle.