𝛃 -sarcoglycanopathy (LGMDR4): a study of muscle diversity using a Sgc𝛃 KO mouse model

Limb Girdle Muscular Dystrophy type R4 (LGMD R4 or β-sarcoglycanopathy) leads to severe muscle degeneration, with poor prognosis in a few years. Despite the genetic mutation, some muscles, like the calf or tongue, resist damage or hypertrophy. Using a Sgcb-null mouse model, we investigated histology and transcriptomics of nine skeletal muscles and the heart at 1, 6 and 12 months. Proximal muscles (e.g., pectoralis, quadriceps) were the most affected, showing degeneration and fibrosis, while distal muscles (e.g., soleus, EDL) were less impacted. Transcriptomic analysis revealed clustering differences in WT muscles, with soleus and diaphragm showing distinct profiles, while KO muscles exhibited greater heterogeneity and dispersed clustering. In KO samples, immune-related pathways were enriched, while processes associated with muscle contraction and energy metabolism were downregulated. For the first time, we identified the sarcoglycan complex enriched at the neuromuscular junction (NMJ), with its localization dependent on nerve presence. Morphological NMJ alterations and reduced membrane potential were observed in KO mice. These findings suggest sarcoglycans at the NMJ may play a role in muscle-specific responses to β-sarcoglycan deficiency, providing new insights into disease heterogeneity.