Sex-specific relationships between muscle damage and regenerative myofiber characteristics post CTX injury
DOI:
https://doi.org/10.58445/rars.4165Keywords:
Muscle Regeneration, Cardiotoxin, Biological Sex, Muscle Damage, Histological AnalysisAbstract
Skeletal muscle regeneration following acute injury relies on highly
coordinated interactions between inflammatory signaling and muscle
tissue responses. Following myofiber necrosis, immune cells infiltrate
the damaged ECM and secrete growth factors like Amphiregulin (Areg),
which can promote satellite cell proliferation and muscle repair.
However, how biological sex and Areg genotype interact to influence
these regenerative processes remains poorly defined. We examined
whether sex and Areg genotype modulate the relationship between tissue
damage and histological measures of regeneration. It was hypothesized
that in a mouse model of CTX-induced injury, female and male mice
across WT and Areg KO genotypes would exhibit sex- and
genotype-dependent differences in the relationship between damaged
area and regenerative myofiber characteristics (size and central
nuclei). Twenty-seven mice were divided across four cohorts: WT males,
WT females, Areg KO males, and KO females. Following CTX-induced
injury, Tibialis Anterior sections were harvested at day 5, stained
with WGA and DAPI, imaged, and analyzed using FIJI to quantify
morphometric parameters. Pearson correlation analyses were performed
separately for each group. A strong inverse correlation between
percent damaged area and median CSA was observed only in WT males (r =
-0.89, p = 0.019). Conversely, percent damaged area positively
correlated with percent central nuclei in WT females (r = 0.87, p =
0.011) and KO females (r = 0.83, p = 0.041). These findings suggest
that Areg signaling and biological sex distinctively shape
regenerative relationships, underscoring the need for multivariate
criteria when evaluating muscle repair.
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