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Gender-Specific Differences in Skeletal Muscle Regeneration

2010; Elsevier BV; Volume: 158; Issue: 2 Linguagem: Inglês

10.1016/j.jss.2009.11.135

1095-8673

Matthew McHale, A.K. Schlechter, Francis M. Torres, Joel Michalek, Linda M. McManus, Paula K. Shireman,

Bone fractures and treatments

Objective(s): Skeletal muscle regeneration is an important component of recovery following traumatic and ischemic injuries; however, the specific role that gender plays in skeletal muscle regeneration remains mostly unidentified. While it is established that gender differences exist in baseline muscle, few studies have addressed potential differences in muscle regeneration, particularly with respect to the morphological changes that occur after injury and during regeneration. This study evaluated inflammatory cell recruitment and the cellular changes that occurred during skeletal muscle regeneration to determine the effect that gender exerted on the robust regenerative potential of muscle. Methods: Injury was induced by cardiotoxin injection into hind limb muscles of 4-6 month old male and female mice (C57Bl/6 J). Tissue levels of monocyte chemotactic protein-1 (MCP-1), macrophages and neutrophils were determined. Histomorphometry was used to estimate regenerated muscle fiber size, adipocyte accumulation, as well as residual necrosis in the tibialis anterior muscles at baseline and various time points following injury. Furthermore, a parallel analysis was conducted on female mice that underwent oopherectomy at 12 weeks of age prior to muscle injury. Results: Tissue levels of MCP-1, macrophages and neutrophils were similar between male and female mice. However, females at days 5 and 7 exhibited less residual necrosis than males (p≤0.05). While baseline fiber size was smaller in females vs males (p<0.001), regenerated myofibers progressively increased in size following injury and were similar between the two groups at all post-injury time points except for an increased size in males at day 21 (p=0.03, Graph A). However, at day 14 post-injury, myofibers in ovariectomized mice were significantly smaller than intact females (p<0.001). Adipocyte accumulation within regenerating muscle was significantly greater in females during the first two weeks following injury compared to males (p≤0.01); oopherectomy led to similar adipocyte accumulation as males, but decreased compared to intact females (p=0.02, Graph B). Conclusions: Intact males and females exhibited equivalent regeneration in regards to fiber size until later time points, reflecting the increased fiber size in males at baseline; however, females demonstrated a significant increase in adipocytes associated with injury. Adipocytes within muscle are generally regarded as a marker of impaired muscle regeneration; nonetheless, females demonstrated a more efficient removal of necrotic tissue after injury despite similar tissue macrophages. This suggests that the earlier resolution of necrosis in females may be related to the increase in adipose tissue. Oopherectomy led to decreased regenerating fiber size and adipocyte accumulation compared to intact females. Thus, removal of ovarian-derived hormones led to impaired muscle regeneration, but less adipocyte accumulation. These studies suggest that recovery from injury is different between males and females, partially due to female hormones, and that gender-specific treatment strategies may be beneficial following ischemic or traumatic muscle injury.