Musculoskeletal (Mal)adaptations in Response to a > 30 000-km Running Challenge.

Background: Ultra-endurance sports are increasingly popular, yet the long-term physiological consequences of sustained extreme training loads remain poorly understood. In particular, the effects of prolonged ultra-endurance exercise on skeletal muscle structure, function and molecular remodelling are largely unknown. This case study examined a highly experienced ultra-endurance athlete who completed a world-record attempt to run 30 300 km, with extensive phenotyping focusing on skeletal muscle adaptations and recovery.

Methods: A 49-year-old male athlete (172 cm, 65 kg) ran ~70 km daily for 15 months. Musculoskeletal, cardiac and visceral ultrasonography, leg muscle strength and power measurements were performed before and after the challenge. Muscle biopsies (n = 4) from vastus lateralis were obtained immediately after completion and during 17 months of recovery to assess myosin heavy chain (MHC) composition, mitochondrial electron transport chain (ETC) complexes and proteins involved in mitochondrial turnover, autophagy and inflammation. Body composition, haematological and biochemical markers, and gut microbiota composition were monitored longitudinally.

Results: The athlete ran 30 300 km over 444 days, maintaining a daily distance of ~70 km despite substantial musculoskeletal discomfort, including a tibial stress reaction mid-challenge, which resolved gradually with continued running. Body mass decreased by ~3 kg, primarily reflecting fat loss (~83%), accompanied by reductions in muscle thickness, maximal strength and power. Circulating creatine kinase (3-15-fold), oxidative stress markers (~50%) and GDF8 (~10%-50%) were sustainedly increased, whereas IGF-I decreased (~10%-40%), suggesting a reduced anabolic environment during the challenge. Muscle biopsy analyses revealed a progressive recovery of mitochondrial function during the 17 months following the challenge, as evidenced by a progressive increase in ETC protein abundance and the expression of regulators of mitochondrial dynamics and quality control (MFN2, PARKIN, DRP1). In contrast, markers of autophagy, apoptosis and inflammation were decreased during the 17-months post-challenge (LC3A/B-I by ~50%, CASP3 by ~60% and NF-κB Ser536 by ~20%). Muscle fibre composition showed extreme predominance of slow fibres (nearly 100% MHC-I), which persisted during recovery. Most molecular and functional alterations gradually resolved within 10-17 months. Gut microbiota diversity increased during the challenge, with enrichment of Bifidobacterium during running and Akkermansia during recovery.

Conclusions: Sustaining daily ultrarunning for more than 1 year induces substantial skeletal muscle remodelling, including reduced muscle size, impaired contractile function and mitochondrial maladaptations, despite largely preserved endocrine and haematological stability. These

Findings: highlight skeletal muscle as a primary physiological system challenged during extreme endurance exercise and demonstrate that recovery from such perturbations may require more than one year.