Evaluating an Exercise Training Approach to Enhance Muscle Function and Mitigate Pathology in Pompe Disease Patients on Enzyme Replacement Therapy

Abstract

Pompe disease (PD) is a lysosomal storage disorder caused by a recessive mutation in the GAA gene encoding acid α-glucosidase, the enzyme responsible for lysosomal glycogen degradation. Reduced enzyme activity leads to glycogen accumulation in skeletal muscle, impaired autophagic flux, enlarged and dysmorphic mitochondria, and increased production of reactive oxygen species (ROS), culminating in progressive muscle weakness. Enzyme replacement therapy (ERT) is the standard treatment; however, despite clinical benefits, it remains largely ineffective in skeletal muscle, and patients continue to experience physical and respiratory decline. Given the central role of muscle in PD pathology, targeted exercise may improve outcomes by enhancing glycogen clearance via autophagy, restoring mitochondrial function, and reducing ROS-mediated damage. This study evaluated a home-based combinatorial intervention of aerobic endurance training (AET), resistance training (RT), and respiratory muscle training (RMT) as an adjunct to ERT in PD. Twenty-two genetically confirmed late-onset Pompe disease (LOPD) patients (21–65 years) on ERT for ≥ 3 months were recruited, along with an age- and sex-matched control group (n = 5) for baseline comparisons. Sixteen patients completed 16 weeks of AET (2×/week cycling at 60-70% Heart rate reserve), full-body RT (4×/week with graded exercise bands), and RMT (4×/week). Pre- and post-testing assessed multiple measures including VO₂peak, strength (Biodex dynamometer), functional capacity (6-minute walk test; 6MWT), and DXA-derived body composition. Significant improvements were observed in leg extension peak torque (+25.4 N•m, +20%, p<0.01), leg press 1-RM (+37 N•m, +17%, p<0.01), and core endurance (+89% sec for plank, +81% sec for abdominal bridge, p < 0.01). Respiratory function increased in seated and supine FVC (+8%, +12%, p < 0.01) and FEV₁ (+4%, +9%, p<0.01), maximal inspiratory pressure (+20%, p<0.01), and maximal expiratory pressure (+15%, p<0.05). Functional performance improved with a +41.0 m (+8%, p<0.01) gain in 6MWT distance. No significant changes were detected in body composition or quality-of-life measures. Safety was confirmed by stable serum AST, ALT, and CK levels. These findings support the feasibility, safety, and efficacy of combined exercise training alongside ERT in LOPD, with further analyses underway to examine cellular and molecular adaptations. This work builds upon prior research and was the first home-based exercise intervention in LOPD to show strength adaptations, advancing mechanistic understanding of mitochondrial and biochemical pathways, and informing the integration of lifestyle interventions to preserve function and prolong health span in neuromuscular diseases and aging.