INTRODUCTION: The relationship between fiber size and myonuclear content is understood poorly.

METHODS: Biopsy cross-sections from young and old trained and untrained healthy individuals were analyzed for fiber area and myonuclei, and 2 fiber size-dependent cluster analyses were performed.

RESULTS: Comparing fibers of similar size, no effect of training or age was found for myonuclear domain. There was a linear relationship between fiber area and myonuclei per fiber (r=0.99; P<0.001) and a non-linear relationship between fiber area and domain (r=0.97-0.99; P<0.0001), with a markedly smaller domain in fibers <3,000 μm(2) . A larger proportion of type II fibers below 3,000 μm(2) was observed in the old.

DISCUSSION: These findings suggest that age-related reductions in myonuclear domain size could be explained by a larger proportion of small fibers and highlight the usefulness of fiber size-based clusters in gaining mechanistic insight into the relationship between skeletal muscle fiber size and myonuclear content.