Estradiol's beneficial effect on murine muscle function is independent of muscle activity

Abstract

Estradiol (E₂) deficiency decreases muscle strength and wheel running in female mice. It is not known if the muscle weakness results directly from the loss of E₂ or indirectly from mice becoming relatively inactive with presumably diminished muscle activity. The first aim of this study was to determine if cage activities of ovariectomized mice with and without E₂ treatment differ. Ovariectomized mice were 19-46% less active than E₂-replaced mice in terms of ambulation, jumping, and time spent being active (P ≤ 0.033). After E₂-deficient mice were found to have low cage activities, the second aim was to determine if E₂ is beneficial to muscle contractility, independent of physical activities by the mouse or its hindlimb muscles. Adult, female mice were ovariectomized or sham-operated and randomized to receive E₂ or placebo and then subjected to conditions that should maintain physical and muscle activity at a constant low level. After 2 wk of hindlimb suspension or unilateral tibial nerve transection, muscle contractile function was assessed. Soleus muscles of hindlimb-suspended ovariectomized mice generated 31% lower normalized (relative to muscle contractile protein content) maximal isometric force than suspended mice with intact ovaries (P ≤ 0.049). Irrespective of whether the soleus muscle was innervated, muscles from ovariectomized mice generated ∼20% lower absolute and normalized maximal isometric forces, as well as power, than E₂-replaced mice (P ≤ 0.004). In conclusion, E₂ affects muscle force generation, even when muscle activity is equalized.

Estradiol modulates myosin regulatory light chain phosphorylation and contractility in skeletal muscle of female mice

“…Our results also indicate that E 2 works through specific kinase signaling pathways involving ER␤ and GPER. These data extend previous reports of E 2 affecting skeletal muscle force generation (16,38,39,43,66) and provide insight into a specific molecular modification of myosin as an underlying mechanism. E 2 , as well as the estrogenic compound genistein, has previously been shown to enhance pRLC in other cell types including mouse cardiac muscle (24,54).…”

“…with sham-operated mice (16,38,39,53,65). It was suggested (41) and subsequently demonstrated that ovarian hormones influence muscle strength by directly affecting the function of contractile proteins (43,66), particularly the structure and function of myosin (38,39).…”

“…For example, declines in strength are accelerated around the time of menopause (35,41,51), and skeletal muscles of postmenopausal women on estrogen-based hormone therapy are stronger than those not on hormone therapy (10,17,49). In mouse models, contractile characteristics are impaired in muscles of ovariectomized compared with sham-operated mice (16,38,39,53,65). It was suggested (41) and subsequently demonstrated that ovarian hormones influence muscle strength by directly affecting the function of contractile proteins (43,66), particularly the structure and function of myosin (38,39).…”

“…Among the ovarian hormones, 17␤-estradiol (E 2 ) appears to be the key hormone, because it reverses muscle weakness and contractile protein dysfunction caused by ovariectomy. Specifically, reduced muscle and contractile protein functions were restored when E 2 was administered to ovariectomized mice (16,38,53). In a chemical model of premature aging, of which the ovaries of young adult mice were locally and specifically induced to be senescent, E 2 treatment improved some muscle contractile functions (18).…”

Skeletal muscle contractile function and neuromuscular performance in Zmpste24 −/− mice, a murine model of human progeria

“…Physical activity Twenty-four-hour cage activity was assessed using open field activity chambers (Med Associates Inc., St. Albans, VT) (Greising et al 2011). Briefly, chambers contain infrared arrays in the x-, y-, and z-axes with two sets of beams in the x-direction, one being elevated to 2.5 or 5.4 cm above the bottom of the cage for Zmpste24 −/− and Zmpste24 +/+ mice, respectively (to account for their body size differences).…”