Skeletal muscle weakness in old mice: Underlying mechanisms.

Abstract

Although muscle atrophy and declining strength are accepted as inevitable concomitants of aging, the mechanisms are not understood. The decrease in maximum isometric force (P$\sb{\rm o})$ is of similar magnitude for many muscles in a variety of animals, but the issue of decreased P$\sb{\rm o}$ per cross-sectional area (CSA) of muscle fibers (specific P$\sb{\rm o})$ remains controversial. The purpose of this study was to determine whether intrinsic changes occur in skeletal muscles with aging. The hypotheses were tested that skeletal muscles in old compared with young or adult mice; (1) generate a lower P$\sb{\rm o}$ and specific P$\sb{\rm o},$ (2) are not different with respect to isometric twitch characteristics and force-shortening velocity relationships, and (3) are composed of two distinct populations of muscle fibers, one with functional characteristics not different from those of fibers in adult animals and one with impaired function. Hypotheses (1) and (2) were tested using electrically activated skeletal muscles from young (2-3 months), adult (9-12 months) and old (26-27 months) specific pathogen free male mice. Experiments were conducted in vitro at 25$\sp\circ$C and both hypotheses were supported. Extracellular factors could not explain the deficit with age in specific P$\sb{\rm o}.$ The third hypothesis was tested using single permeabilized muscle fibers activated by calcium. Forces were measured during isometric and isovelocity shortening and lengthening contractions. During isometric and isovelocity shortening contractions, specific forces were not different for fibers from muscles of adult and old mice. In contrast, forces during lengthening contractions were $\sim$10% greater for fibers from muscles of old compared with adult mice. A computer simulation tested the hypothesis that a population of atrophic, nonfunctional fibers in the muscles of old mice was not identified experimentally due to their small CSAs, and that these fibers accounted for the 22% deficit observed for whole muscle specific P$\sb{\rm o}.$ The simulation required that 40% of the muscle fibers of old mice generate zero force and the hypothesis that the deficit in specific P$\sb{\rm o}$ was due exclusively to a population of small denervated fibers was rejected. Although single permeabilized fibers from muscles of old mice generated control values for specific P$\sb{\rm o},$ they were distinguishable from fibers of adult mice based on the force developed during lengthening contractions.