Different responses of skeletal muscles to femoral artery ligation-induced ischemia identified in BABL/c and C57BL/6 mice

Abstract

Peripheral arterial disease (PAD) is a common circulatory problem in lower extremities, and the murine ischemic model is used to reproduce human PAD. To compare strain differences of skeletal muscle responses to ischemia, the left femoral artery was blocked by ligation to reduce blood flow to the limb of BALB/c and C57BL/6 mice. After 6 weeks of the femoral artery ligation, the functional and morphological changes of the gastrocnemius muscle were evaluated. BALB/c mice displayed serious muscular dystrophy, including smaller myofibers (524.3 ± 66 µM2), accumulation of adipose-liked tissue (17.8 ± 0.9%), and fibrosis (6.0 ± 0.5%), compared to C57BL/6 mice (1,328.3 ± 76.3 µM2, 0.27 ± 0.09%, and 1.56 ± 0.06%, respectively; p < 0.05). About neuromuscular junctions (NMJs) in the gastrocnemius muscle, 6 weeks of the femoral artery ligation induced more damage in BALB/c mice than that in C57BL/6 mice, demonstrated by the fragment number of nicotinic acetylcholine receptor (nAChR) clusters (8.8 ± 1.3 in BALB/c vs. 2.5 ± 0.7 in C57BL/6 mice, p < 0.05) and amplitude of sciatic nerve stimulated-endplate potentials (EPPs) (9.29 ± 1.34 mV in BALB/c vs. 20.28 ± 1.42 mV in C57BL/6 mice, p < 0.05). More importantly, 6 weeks of the femoral artery ligation significantly weakened sciatic nerve-stimulated skeletal muscle contraction in BALB/c mice, whereas it didn’t alter the skeletal muscle contraction in C57BL/6 mice. These results suggest that the femoral artery ligation in BALB/c mice is a useful animal model to develop new therapeutic approaches to improve limb structure and function in PAD, although the mechanisms about strain differences of skeletal muscle responses to ischemia are unclear.

The BALB/c.mdx62 mouse exhibits a dystrophic muscle pathology and is a model of Duchenne muscular dystrophy

“…Individual immune responses vary greatly in the human population, and immune response variability to some therapies, particularly viral-mediated interventions, has led to a shortfall in successful translation to the clinic and may limit the dose that can be safely administered to patients. Furthermore, the skeletal muscles of BALB/c mice have been reported to have a reduced regenerative capacity after femoral artery ligation compared to those of C57BL/6 mice ( Tu et al, 2022 ) and, thus, it may be expected that the dystrophic progression varies between different mouse strains. Preclinical analysis of interventions in DMD mouse models across multiple background strains with varying immune profiles and regenerative capacity, are perhaps more closely representative of variations in patient populations and may improve translation to the clinic.…”