Biology subjects

Pyle, W. G.

Publications and source records attributed to Pyle, W. G..

4 recordsLinked to original sources

bioRxiv2024

Investigating the temporal effects of ovarian failure on single muscle fibre contractility using a chemically-induced ovarian failure model in mice

We investigated the effects of chemically-induced ovarian failure on single muscle fibre contractility of the soleus and extensor digitorum longus (EDL) muscles throughout ovarian failure, thereby mimicking the menopausal transition into late-stage menopause: [(D60;peri-menopause), (D120;onset of menopause), (D134;early-onset menopause), (D176;late-stage menopause)]. We used 4-vinylcyclohexene diepoxide (VCD) to induce ovarian failure in sexually-mature female mice. At D120 and D176, mice with VCD-induced ovarian failure produced higher force as compared with controls (p<0.05). On D134, however, VCD had lower force production compared with controls (p<0.05). The cross-sectional area of the soleus fibres from the VCD group was larger at D120 compared with controls (p<0.05), but not at any other time point (p>0.05). As well, at D120-D176, the proportion of Type II fibres relative to Type I increased for the soleus, but not the EDL. No differences in rate of force redevelopment (Ktr) was observed for the soleus (p>0.05), while calcium sensitivity increased by late-stage menopause (p<0.05). There were no differences in force, cross-sectional area, stiffness, Ktr, or calcium sensitivity between groups for the EDL (p>0.05). Muscle contractility across the peri-menopausal transition into late-stage menopause is both muscle and phase-dependent, emphasizing the complexity of changing hormones throughout the lifespan on muscle contractile function.

physiology↗

bioRxiv2023

The Effect of Gradual Ovarian Failure on Dynamic Muscle Function and the Role of High Intensity Interval Training on Mitigating Impairments

Skeletal muscle function is impaired in menopause and exercise may mitigate tshis decline. We used the VCD model of menopause to investigate the effects of gradual ovarian failure on skeletal muscle contractile function and whether high intensity interval training (HIIT) can mitigate impairments. Sexually mature female CD-1 mice were assigned to one of three groups: control (n=5), VCD-sedentary (n=5), or VCD-training (n=5). Following ovarian failure, the VCD-training group underwent 8 weeks of uphill HIIT. Mice were sacrificed 8 weeks after ovarian failure, representing late menopause. Single muscle fibres from the soleus (SOL) and extensor digitorum longus (EDL) muscles were dissected, chemically permeabilized, and mechanically tested. Single muscle fibres were maximally activated (pCa 4.5) then isotonic load clamps were performed to calculate force-velocity-power curves. Absolute force and peak power were 31% and 32% lower in VCD-sedentary fibres compared to control fibres, respectively, in both SOL and EDL muscles. Despite reductions in absolute force and therefore lighter relative loads imposed during the isotonic contractions in VCD-sedentary fibres, there were no concomitant increases in contractile velocity. HIIT was partially effective at mitigating power loss (22% higher peak power in VCD-training compared to VCD-sedentary), but only in fast-type SOL fibres. These findings indicate that ovarian failure impairs dynamic contractile function - likely through a combination of lower force-generating capacity and slower shortening velocity - and that HIIT may be insufficient to completely counteract the deleterious effects of menopause at the cellular level. New & NoteworthyO_LIReductions in circulating ovarian hormones impair static muscle contractile performance, but less is known about dynamic properties like power. C_LIO_LITypically, rodent models of menopause completely remove the ovaries and fail to mimic the prolonged and complex hormonal transition that includes a retention in ovarian androgen production. C_LIO_LIUsing an ovary intact VCD model of ovarian failure, we found that single fibre power was impaired compared with controls in both SOL and EDL fibres. C_LIO_LIOur uphill high intensity interval training program was partially sufficient to reverse power loss, but only in fast-type SOL fibres. C_LIO_LIImpairments in muscle power following ovarian failure are likely driven by a combination of decreased muscle size and force-generating capacity. C_LI

physiology↗

bioRxiv2023

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

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 (P<0.05), respectively, with no differences in force produced by the EDL fibers across groups (P>0.05). 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.

physiology↗

bioRxiv2020

Cardiac CapZ regulation during acute exercise

PurposeExercise requires a rapid cardiac response to maintain cardiovascular function. CapZ is a critical stress-response protein in cardiac myocytes. While its role in the pathological stress response has been explored, its part in the physiological response to exercise is unknown. This study examined CapZ regulation during acute exercise and sought to determine its importance in the cardiac response to exercise. MethodsWildtype or cardiac CapZ-deficient transgenic mice were subjected to 20 min of swimming, or exhaustive exercise protocols. Time to exhaustion was a measurement of exercise capacity. Following submaximal exercise, cardiac myofilaments were isolated and probed for CapZ and key regulatory proteins. Myofilament function was assessed using an actomyosin MgATPase assay and total protein phosphorylation quantified with ProQ Diamond staining. Myofilament regulatory proteins following submaximal exercise were quantified by immunoblotting. ResultsTotal myofilament CapZ was unaffected by exercise but increased total CapZIP and decreased phosphorylated CapZIP indicated weakened CapZ-actin interaction. CapZ-deficient transgenic myofilaments lacked changes in CapZIP but BAG3 increased 10%. Time to exhaustion was lower in CapZ-deficient mice in both swimming and running protocols. Actomyosin MgATPase activity was maintained in wildtype mice and impaired with CapZ deficiency. Exercise increased the phosphorylation of several myofilament proteins in wildtype mice but not transgenic animals. Exercise-dependent Increases in myofilament PKC- and -{varepsilon} were mitigated in CapZ-deficient mice. Tcap levels decreased 39 {+/-} 8% in CapZ-deficient myofilaments with exercise and leiomodin 2 increased 78 {+/-} 28% in wildtype myofilaments. ConclusionsCardiac CapZ is a critical player in the physiological response to exercise. CapZ-actin binding is rapidly altered with exercise. Decreased cardiac CapZ limits exercise capacity, impairs myofilament regulation, and leads to a less stable contractile apparatus.

physiology↗