A High-Fat/High-Sugar Diet Is Associated with Reduced Motor Unit Number and Neuromuscular Dysfunction in Late-Middle-Aged Female Rats: A Pilot Study.

Background: Aging is characterized by metabolic dysfunction and neuromuscular decline, and obesogenic diets may exacerbate these processes. High-fat, high-sugar diets (HFHSD) promote adiposity, systemic metabolic dysregulation, and skeletal muscle impairments, yet their impact on motor unit integrity and neuromuscular vulnerability during aging remains unclear. Methods: In a controlled preclinical experiment, late-middle-aged (15-mo-old) female F344 rats were randomized to HFHSD (n = 6) or regular chow (n = 6) for 10 weeks. Longitudinal assessments were conducted at baseline, 6 weeks, and 10 weeks and included body composition, motor unit number estimation (MUNE), forelimb and hindlimb grip strength, gastrocnemius tetanic contractile torque, and post-intervention electrical impedance myography (EIM). Data were analyzed using a two-way mixed-effects ANOVA to assess the effects of diet and time, with statistical significance set at p < 0.05. Results: HFHSD led to significant increases in body mass and adiposity measures (e.g., abdominal circumference, skinfold thickness). Compared with controls, HFHSD rats exhibited significant reductions in hindlimb MUNE (diet effect, p = 0.007) and decreased tetanic contractile torque in both absolute and body mass-normalized values (p ≤ 0.002). Absolute forelimb grip strength increased over time (p = 0.027), though this effect did not persist after normalization to body mass, and hindlimb grip strength did not differ between groups. EIM at 50 kHz revealed elevated resistance in HFHSD rats (p = 0.0497), whereas reactance and phase angle did not differ significantly. Conclusions: This pilot study provides preliminary evidence that an HFHSD, initiated during late middle age, may accelerate neuromuscular decline in female F344 rats prior to the typical onset of age-associated motor unit loss. A 10-week HFHSD intervention was associated with reductions in estimated motor unit numbers, impairments in muscle contractility, and a dissociation between absolute and normalized forelimb grip strength outcomes, indicating a potential early vulnerability of the neuromuscular system to obesogenic dietary exposure. These findings should be interpreted within the context of a modest sample size but collectively support the concept that diet-induced metabolic dysfunction may contribute to early neuromuscular impairment during aging.