Age- & Sex-specific Effects of Trimetazidine Dihydrochloride on Fast- and Slow-muscle Contractility in F344/BN Rats
Authors: Russ David , Mifsud Mia , Patek Leah , Sehested Courtney , Deschenes Michael , Weisleder Noah 
Published: May 2023

This study tests the effect of trimetazidine dihydrochloride (TMZ) on contractility in fast and slow skeletal muscles of adult (Ad, 6-8 mo.) and aged (Ag, 75% lifespan) male (M) and female (F) F344/BN rats. We hypothesized that TMZ would enhance contractility produced by indirect, but not direct, stimulation. Methods: Rats were injected with 3 mg/kg TMZ or vehicle 2x/d x 4 wk. Grip strength was assessed at the start and end of the protocol. Ex vivo force was tested at 4 wks in extensor digitorum longus (EDL) and soleus (SOL) at 3 frequencies (EDL: 1, 30, 120Hz; SOL: 1, 15, 60Hz) of direct/muscle and indirect/nerve stimulation. Fiber type was assessed via myosin heavy chain immunostaining. Results: Indirect vs. Direct Stimulation : Higher forces were seen with direct vs. indirect stimulation (P ≤ 0.002). Only tetanic stimulation (120 & 60 Hz, EDL & SOL, respectively) showed effects of age, sex or TMZ on the ratio of indirect/direct stimulation force, which was reduced with age (SOL: 4.9%, P = 0.038; EDL: 5.1%, P = 0.052). EDL Force : Force, but not muscle quality (force/cross-sectional area), was lower in F at all frequencies. No effects of age or TMZ were present for either force or muscle quality. Force at 1 and 120Hz exhibited significant Age X Sex interactions (P = 0.029 & 0.013). Age X Sex X TMZ interaction was significant at 30 and 120Hz (P = 0.028 & 0.046). In contrast, only muscle quality at 120-Hz exhibited any effects (P = 0.024; Age x Sex), There was also a trend (P = 0.067) for TMZ to reduce muscle quality at 120-Hz stimulation. The general trend was for Ag M to exhibit reduced force and muscle quality vs. Ad M, with increases in Ag vs. Ad F. SOL Force : A significant effect of sex on peak force was present at all frequencies tested. An effect for TMZ was present at 60-Hz (P = 0.024), largely due to lower force in TMZ-treated F. Muscle quality showed a main effect of TMZ and the Sex X TMZ interaction (P = 0.007 & 0.048,), due reductions in TMZ-treated F. Grip Strength : An age X sex interaction was found (P = 0.012), but TMZ exhibited only trends for interaction effects (Age x TMZ, P = 0.084; Time x Age x Sex x TMZ, P = 0.062). Grip strength normalized to body mass, showed a similar Time x Age x Sex x TMZ interaction (P = 0.062). Fiber Type : Effect of Sex and a Sex X TMZ interaction were observed for percent Type IIa and Type IIb fibers in the EDL. TMZ tended to increase % IIa fibers in M, while decreasing it in F, with the reverse seen for % Type IIb fibers. Conclusions: Indirect/direct stimulation data suggest age-related impairment in peripheral neural activation that is not affected by TMZ. TMZ improved grip less than in previous studies and produced smaller effects on contractility than sex or age. In fact, TMZ tended to reduce contractility, particularly in the SOL. However, TMZ did influence EDL fiber type in a sex-dependent manner which may influence differences in contractility. NIH/NIA R03 AG060143-01A1 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.