Increased Adipocyte Area in Injured Muscle With Aging and Impaired Remodeling in Female Mice

Abstract

We demonstrated that young male and female mice similarly regenerated injured skeletal muscle; however, female mice transiently increased adipocyte area within regenerated muscle in a sex hormone-dependent manner. We extended these observations to investigate the effect of aging and sex on sarcopenia and muscle regeneration. Cardiotoxin injury to the tibialis anterior muscle of young, middle, and old-aged C57Bl/6J male and female mice was used to measure regenerated myofiber cross-sectional area (CSA), adipocyte area, residual necrosis, and inflammatory cell recruitment. Baseline (uninjured) myofiber CSA was decreased in old mice of both sexes compared to young and middle-aged mice. Regenerated CSA was similar in male mice in all age groups until baseline CSA was attained but decreased in middle and old age female mice compared to young females. Furthermore, adipocyte area within regenerated muscle was transiently increased in young females compared to young males and these sex-dependent increases persisted in middle and old age female mice and were associated with increased Pparg Young female mice had more pro-inflammatory monocytes/macrophages in regenerating muscle than young male mice and increased Sca-1(+)CD45(-)cells. In conclusion, sex and age influence pro-inflammatory cell recruitment, muscle regeneration, and adipocyte area following skeletal muscle injury.

Absence of CCR2 results in an inflammaging environment in young mice with age-independent impairments in muscle regeneration

“…males and females across the 3 age groups were comparable, whereas both sexes exhibited an increased (P # 0.002) ratio in young compared with both middle-and old-age groups. Thus, whereas anterior compartment weight decreased with age, body weight increased until middle age and decreased thereafter, which suggests that young mice had relatively heavier anterior compartments for their body weight compared with middle-and old-age mice, consistent with a loss in muscle mass observed in sarcopenia [2,49,50].…”

“…Concurrently, skeletal muscle progenitor cells, also known as satellite cells, proliferate and migrate to the area of injury, differentiate, and merge to form myofibers. Impressively, this elaborate and complex process is primarily complete by 7 d, with myofiber CSA reaching baseline by ;21-28 d in young mice [2][3][4][5]. Mechanisms of regeneration across aging and sex that contribute to dysfunction in regeneration are highly debated and poorly understood, which impedes progress in devising therapies for muscle regeneration.…”

“…However, young female mice more effectively cleared necrotic tissue but exhibited increased adipocyte area in regenerated muscle compared with males, with adipocyte area differences dependent upon having intact gonads [4], which suggested sex-specific differences in regeneration. Whereas young females were able to eventually remodel the regenerated tissue to decrease adipocyte area, female mice in middle and old ages retained the adipocytes and exhibited modest impairments in muscle regeneration as measured by regenerated myofiber CSA [2]. Of interest, old age mice with sarcopenia maintained the ability to efficiently regenerate muscle after extensive injury [2,8].…”

“…Whereas young females were able to eventually remodel the regenerated tissue to decrease adipocyte area, female mice in middle and old ages retained the adipocytes and exhibited modest impairments in muscle regeneration as measured by regenerated myofiber CSA [2]. Of interest, old age mice with sarcopenia maintained the ability to efficiently regenerate muscle after extensive injury [2,8].…”

“…Age-related deficits in skeletal muscle regeneration [9][10][11], consistent with the necessity of satellite cells to regenerate [12][13][14], have focused on age-related decreases in number and/ or function of satellite cells [15][16][17][18][19][20]. However, minimal deficits in muscle regeneration with aging have been demonstrated by using myofiber CSA [2] or restoration of tissue architecture and function between young and old animals [8]. Even studies that focused on ex vivo satellite cells or tissue explants from animal models and humans observed no aging deficit when cultures were maintained in standard conditions [21,22] or in cultures that contained human sera from young vs. old humans [23].…”