Metabolic reprogramming underlies cavefish muscular endurance despite loss of muscle mass and contractility

Abstract

Physical inactivity - specifically the lack of moderate-to-vigorous activity — is a scourge to human health, promoting metabolic disease and muscle wasting. Interestingly, multiple ecological niches have relaxed investment into physical activity, providing unique evolutionary insight into adaptive physical inactivity. The Mexican cavefish Astyanax mexicanus lost moderate-to-vigorous activity following cave colonization, reaching basal swim speeds ~3-fold slower than their river-dwelling counterpart. We found that this was accompanied by a marked shift in body composition, decreasing muscle mass by 30% and increasing fat mass by 40%. This shift persisted at the single muscle fiber level via increased lipid and sugar accumulation at the expense of myofibrillar volume. Transcriptomic analysis of laboratory-reared and wild-caught cavefish indicated this shift in investment is driven by increased expression of pparγ — the master regulator of adipogenesis — with a simultaneous decrease in fast myosin heavy chain expression. Ex vivo and in vivo analysis confirmed these investment strategies come with a functional trade-off, decreasing cavefish muscle fiber shortening velocity, time to maximal force, and ultimately maximal swimming velocity. Despite this, cavefish displayed a striking degree of muscular endurance, reaching maximal swim speeds ~3.5-fold faster than their basal swim speeds. Multi-omics analysis indicated metabolic reprogramming, specifically increased phosphoglucomutase-1 abundance, phosphorylation, and activity, as contributing mechanisms enhancing cavefish glycogen utilization under metabolically strenuous conditions. Collectively, we reveal broad skeletal muscle reprogramming following cave colonization, displaying an adaptive skeletal muscle phenotype reminiscent to mammalian disuse and high-fat models while simultaneously maintaining a unique capacity for sustained muscle contraction under fatiguing conditions.

Muscle power production during intermittent swimming in bluegill sunfish

“…Individual muscle bundles (two per fish) were dissected from the strips; each bundle was one myomere of muscle approximately 4 mm in length and 0.5 × 0.5 mm in cross‐section. The bundles (16 bundles total = 8 fish × 2 bundles per fish) were tied into a muscle mechanics apparatus composed of a servomotor, force transducer, temperature‐controlled chamber filled with recirculating physiological saline and platinum‐stimulating electrodes (see Olsen et al, 2023, for details and diagram of the apparatus). Experimental control was carried out using a PC and Dynamic Muscle Control software (Aurora Scientific).…”

The Mexican Cavefish Mount a Rapid and Sustained Regenerative Response Following Skeletal Muscle Injury

“…These caves are completely devoid of light, resulting in diminished primary producers and a subsequent general lack in biodiversity. These different selective pressures have led to many cave-specific morphological and physiological adaptations (Krishnan et al 2020; Stockdale et al 2028; Peuß et al 2020; Olsen et al 2022). For example, we found that the diminished macroparasite diversity in certain caves affected the evolution of the immune investment strategy and the sensitivity of the immune system towards immunological stimuli (e.g.…”