Effects of VCD-induced ovarian failure on single muscle fiber contractility in a mouse model of menopause

Abstract

ObjectiveMenopause is associated with impairments in muscle contractile function. The temporal and mechanistic basis of this dysfunction are not known. Using a mouse model of menopause we identified how gradual ovarian failure affects single muscle fiber contractility. Study designMice were injected with VCD over 15 days and ovarian failure developed over 120 days. Mice were then sacrificed and slow-type soleus (SOL) and fast-type extensor digitorum longus (EDL) muscles were dissected and chemically permeabilized for mechanical testing. Main outcome measuresMuscle fiber contractility was assessed via: force, rate of force redevelopment, instantaneous stiffness, and calcium sensitivity across three relative force levels (pCa10,pCa50,pCa90). ResultsPeak force and cross-sectional area (CSA) of the SOL were [~]33% and [~]24% greater in the VCD group as compared with controls (P0.05). Upon normalizing force to CSA there were no differences across groups (P>0.05). Rate of force development was [~]33% faster for SOL in the VCD group compared to control. Ca2+ sensitivity did not differ between groups for either muscle at pCa50 (P>0.05). In the VCD group, Ca2+ sensitivity was higher for EDL, but lower for SOL at pCa10 and pCa90 (P<0.05), respectively. ConclusionsIn our mouse model of menopause, alterations to muscle contractility were much less evident as compared with ovariectomized models. This divergence across models highlights the importance of better approximating the natural trajectory of menopause during and after the transitional phase of ovarian failure on neuromuscular function.