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

Abstract

Physical inactivity is a scourge to human health, promoting metabolic disease and muscle wasting. Interestingly, multiple ecological niches have relaxed investment into physical activity, providing an evolutionary perspective into the effect of adaptive physical inactivity on tissue homeostasis. One such example, the Mexican cavefish Astyanax mexicanus, has lost moderate-to-vigorous activity following cave colonization, reaching basal swim speeds ~3.7-fold slower than their river-dwelling counterpart. This change in behavior is accompanied by a marked shift in body composition, decreasing total muscle mass and increasing fat mass. 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 that this shift 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 that these investment strategies come with a functional trade-off, decreasing cavefish muscle fiber shortening velocity, time to maximal force, and ultimately maximal swimming speed. Despite this, cavefish displayed a striking degree of muscular endurance, reaching maximal swim speeds ~3.5-fold faster than their basal swim speeds. Multi-omic analysis suggested metabolic reprogramming, specifically phosphorylation of Pgm1-Threonine 19, as a key component enhancing cavefish glycogen metabolism and sustained muscle contraction. Collectively, we reveal broad skeletal muscle changes 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 via enhanced glycogen metabolism.

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.…”

White epaxial muscle aerobic and anaerobic potential and muscle fiber structure in surface and cave morphotypes of the Mexican cavefish (Astyanax mexicanus)

“…We found that cave morphotypes have larger muscle fiber diameter, though, not significantly larger compared with the surface morphotypes. Others have found a significant increase in muscle fiber cross‐sectional area in lab‐reared cave morphotypes compared with surface morphotypes (Olsen et al, 2023), however, our methods for determining muscle fiber size and Olsen et al (2023) are different. For cave morphotypes, a selective advantage for decreasing metabolic costs may be associated with their low O 2 and nutrient environment (Boggs & Gross, 2021; Maldonado et al, 2020), and increased concentration of glycogen (Olsen et al, 2023).…”

Circadian rhythm disruption is associated with skeletal muscle dysfunction within the blind Mexican Cavefish

“…In fact, disruption of the skeletal muscle circadian rhythm results in insulin resistance, sarcomere disorganization, and muscle weakness in both vertebrates and non-vertebratesindicating that maintenance of a functional muscle circadian rhythm provides an adaptive advantage. We and others have found that cavefish possess a disrupted central circadian rhythm and, interestingly, a skeletal muscle phenotype strikingly similar to circadian knock-out mutants; namely, muscle loss, muscle weakness, and insulin resistance (Olsen et al 2022;Riddle et al 2018;Mack et al 2021). However, whether the cavefish muscle phenotype results from muscle-specific circadian disruption remains untested.…”

“…In fact, amino acid levels are under circadian control, with their rhythmicity coinciding with proteasomal gene expression (Eckel-Mahan et al 2013). Recent metabolomic analysis from our group underscores this relationship, finding reduced cavefish muscle free amino acid levels coupled with decreased muscle mass and contractility (Medley et al 2022;Olsen et al 2022). For example, the anabolic amino acid leucine is decreased ~2-fold within cavefish skeletal muscle, with its transporter (slc7a8) lacking rhythmicity exclusively within cavefish (Fig.…”