Journal Article

Skeletal Muscle miRNA Patterns in High-Altitude Trekkers: Exploratory Identification of Molecular Signatures of Cellular and Endocrine Adaptation

Bondi, Danilo, Cocci, Paolo, Verratti, Vittore, Marramiero, Lorenzo, Palermo, Francesco Alessandro, Santangelo, Carmen, Pietrangelo, Tiziana

2026

Overview

Exposure to high-altitude hypoxia leads to complex physiological and molecular adaptations, particularly in skeletal muscle. MicroRNAs (miRNAs), including muscle-enriched (myomiRNAs) and hypoxia-responsive (hypoxamiRNAs), play critical roles in regulating these responses. We investigated miRNA expression changes in the skeletal muscle of healthy, non-smoking Italian adults (mean age 36.7 ± 12.4 years) participating in the Himalayan expedition “Lobuche Peak—Pyramid Exploration & Physiology” conducted in the Sagaramāthā (Mount Everest) National Park, Nepal. The peak overnight stay altitude was ≈5000 m at the Pyramid International Laboratory—Observatory. Muscle biopsies were taken before and after the expedition from Vastus lateralis, at one-third of the distance from the upper margin of the rotula to the anterior superior iliac spine. Small RNA sequencing was used to profile differentially expressed miRNAs. Several miRNAs were differentially expressed (exploratory analysis), suggesting potential involvement in hypoxia-related adaptation. These encompass both canonical myomiRNAs (e.g., miR-206, miR-486-5p) and hypoxamiRNAs (e.g., miR-378a-5p, miR-199a-3p, let-7b-5p). In enrichment analysis, we found several connections between miRNAs and pathways that may play a role in physiological regeneration or differentiation in muscle cells. Among functions, focal adhesion (p-value = 0.001), regulation of actin cytoskeleton (p-value = 0.026), Rap-1 (p-value = 0.007), cAMP (p-value = 0.017), MAPK (p-value = 0.019), and Hippo (p-value = <0.001) signaling pathways were predicted to be the most targeted. These findings provide preliminary insights into physiological adaptation, requiring confirmation in larger and controlled cohorts.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Actin / Adaptation / Adaptation, Physiological - genetics / Adult / Altitude / Analysis / biomarkers / Biopsy / Cell differentiation / Chronic illnesses / Cyclic adenylic acid / Cytoskeleton / Ethylenediaminetetraacetic acid / Exercise / extreme environments / Female / Gene Expression Profiling / Gene Expression Regulation / High-altitude environments / high-altitude hypoxia / Humans / Hypoxia / Hypoxia - genetics / Hypoxia - metabolism / Male / MAP kinase / Metabolism / MicroRNA / microRNA (miRNA) / MicroRNAs / MicroRNAs - genetics / MicroRNAs - metabolism / Middle Aged / miRNA / Mountaineering / Muscle proteins / Muscle, Skeletal - metabolism / Muscles / Musculoskeletal system / National parks / Penicillin / Physiological aspects / Physiology / RNA sequencing / Sample size / Skeletal muscle