Mechanisms of Fatigue with Aging: Evidence from the Whole-Limb to the Single Cell in Humans

Aging is accompanied by a loss of muscle mass and increased fatigability of limb muscles making it difficult for old adults to generate the force and power necessary to perform daily activities, such as ascending a flight of stairs. The mechanisms for the age-related increase in fatigability in old and very old adults (≥80 yrs) and whether there are differences between men and women are unknown. The purpose of this dissertation was to determine the mechanisms for the age-related increase in fatigability in men and women by studying fatigue at the level of the whole-limb and within the muscle cells. Study one compared the fatigability of the knee extensor muscles and determined the mechanisms of fatigue in young, old, and very old men and women elicited by high-velocity exercise. Fatigability of the whole-limb increased across age groups, with no sex differences observed in any age cohort. The age-related increase in power loss was strongly associated with changes in involuntary muscle contractile properties, with minimal contribution from age differences in neural drive. These data suggest the increased fatigability with aging is determined primarily by mechanisms within the muscle for both sexes. To test whether cross-bridge mechanisms could explain the age-related losses in whole-muscle power and increased fatigability, muscle cells from vastus lateralis biopsies were exposed to conditions mimicking quiescent muscle and fatiguing levels of hydrogen (H+) and phosphate (Pi). The fatigue-mimicking conditions revealed that H+ and Pi act synergistically to cause marked reductions in human cross-bridge function. However, other than severe atrophy of fast fibers in old men and women, the effects of the fatigue conditions on cross-bridge function with either severe (study 2) or a range of elevated H+ and Pi (study 3) did not differ with age. These data suggest that age-related losses in whole-muscle power are due primarily to atrophy of fast fibers, but the age-related increase in fatigability cannot be explained by an increased sensitivity of the cross-bridge to H+ and Pi. Combined, these studies suggest that interventions targeting the muscle are necessary to mitigate age-related declines in power and increased fatigability in men and women