Skeletal Muscle Fatigue: Mechanisms And Mitigation At The Cellular And Molecular Levels In Older Adults

Abstract

Skeletal muscle fatigue, or the contraction-induced decline in whole muscle force or power, decreases physical function in older adults. Fatigue primarily results from elevated hydrogen (H+) and phosphate (Pi) altering myosin-actin interactions; however, which steps of the myosin-actin cross-bridge cycle are altered and whether these changes are reversible at the molecular and cellular levels are unclear. PURPOSE: The study objectives were to: 1) Examine the effects of simulated fatigue on molecular and cellular function, and 2) Test the ability of deoxyadenosine triphosphate (dATP), an alternative energy to adenosine triphosphate (ATP), to reverse fatigue-induced changes. METHODS: Maximal force production, myofilament mechanics and cross-bridge kinetics were measured in single fibers (20 per person) from the vastus lateralis of 8 (4 men) healthy, sedentary older adults (65-75 years) under normal (5 mM Pi, pH 7.0), fatigue (30 mM Pi, pH 6.2) and fatigue with dATP conditions. ANOVAs with post-hoc tests were used to evaluate differences between means by fiber-type and results were considered significant at P ≤ 0.05. RESULTS: Force declined with fatigue in slow- (myosin heavy chain (MHC) I, 22%) and fast-contracting (MHC II, 30%) fibers due to a reduced number or stiffness of strongly bound myosin heads (30-36%) and slower cross-bridge kinetics (longer myosin attachment times (18-31%) and reduced rates of force production (17-37%)). MHC I myofilaments became stiffer with fatigue (59%), suggesting a fiber-type specific mechanism to partially mitigate fatigue-induced force reduction. Fatigue with dATP moderately improved force production similarly in both fiber types (10-12%) compared to fatigue with ATP. In MHC I fibers, fatigue with dATP returned the number or stiffness of myosin heads and cross-bridge kinetics to normal values. In MHC II fibers, fatigue with dATP left the number or stiffness of myosin heads similar to fatigue conditions, while the cross-bridge kinetics were 19-22% faster than normal. CONCLUSION: These results identify novel fiber-type specific changes in myosin-actin interactions and myofilament stiffness that help explain fatigue-related force reduction in older adults as well as an alternative energy source that partially reverses the effects of fatigue. Supported by: NIH AG047245