title: Skeletal muscle metabolic adaptations to endurance exercise training are attainable in mice with simvastatin treatment.
abstract: We tested the hypothesis that a 6-week regimen of simvastatin would attenuate skeletal muscle adaptation to low-intensity exercise. Male C57BL/6J wildtype mice were subjected to 6-weeks of voluntary wheel running or normal cage activities with or without simvastatin treatment (20 mg/kg/d, n = 7-8 per group). Adaptations in in vivo fatigue resistance were determined by a treadmill running test, and by ankle plantarflexor contractile assessment. The tibialis anterior, gastrocnemius, and plantaris muscles were evaluated for exercised-induced mitochondrial adaptations (i.e., biogenesis, function, autophagy). There was no difference in weekly wheel running distance between control and simvastatin-treated mice (P = 0.51). Trained mice had greater treadmill running distance (296%, P<0.001), and ankle plantarflexor contractile fatigue resistance (9%, P<0.05) compared to sedentary mice, independent of simvastatin treatment. At the cellular level, trained mice had greater mitochondrial biogenesis (e.g., ~2-fold greater PGC1α expression, P<0.05) and mitochondrial content (e.g., 25% greater citrate synthase activity, P<0.05), independent of simvastatin treatment. Mitochondrial autophagy-related protein contents were greater in trained mice (e.g., 40% greater Bnip3, P<0.05), independent of simvastatin treatment. However, Drp1, a marker of mitochondrial fission, was less in simvastatin treated mice, independent of exercise training, and there was a significant interaction between training and statin treatment (P<0.022) for LC3-II protein content, a marker of autophagy flux. These data indicate that whole body and skeletal muscle adaptations to endurance exercise training are attainable with simvastatin treatment, but simvastatin may have side effects on muscle mitochondrial maintenance via autophagy, which could have long-term implications on muscle health.
authors.affiliation: Department of Kinesiology, University of Georgia, Athens, Georgia, United States of America.
authors.forename: William M
authors.initials: WM
authors.lastname: Southern
authors.affiliation: Department of Kinesiology, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Nichenko
authors.affiliation: Department of Kinesiology, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Shill
authors.affiliation: Department of Kinesiology, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Corey C
authors.initials: CC
authors.lastname: Spencer
authors.affiliation: Department of Kinesiology, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Nathan T
authors.initials: NT
authors.lastname: Jenkins
authors.affiliation: Department of Kinesiology, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: McCully
authors.affiliation: Department of Kinesiology, University of Georgia, Athens, Georgia, United States of America.|Regenerative Bioscience Center, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Jarrod A
authors.identifier: http://orcid.org/0000-0002-1094-4940
authors.initials: JA
authors.lastname: Call
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001343:Autophagy; D000071183:Autophagy-Related Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects*; D009119:Muscle Contraction / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D012420:Running; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D000924:Anticholesteremic Agents; D000071183:Autophagy-Related Proteins; D019821:Simvastatin