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The main goal of the study was to explore the genetic architecture underlying muscle weight in old mice. Weight of soleus, tibialis anterior (TA), extensor digitorum longus (EDL), and gastrocnemius muscles was measured in the C57BL/6J (B6) and DBA/2J (D2) strains and derivative generations: a panel of the BXD recombinant inbred (RI) strains and a B6D2 F(2) intercross at the age of 800 days. The between-strain difference in muscle weight (B6 > D2) ranged between 16% and 38%. Linkage analysis identified suggestive quantitative trait loci (QTL) on Chromosomes (Chr) 2, 6, 7, 8, 19, and X that influenced muscle weight in the 800-day-old group. Comparison of weights at 200, 500, and 800 days revealed a variable effect of age among the four muscles. Linkage analysis in the B6D2 F(2) population combined across the three different age groups identified muscle-, sex-, and age-specific QTL on Chr 1, 2, 3, 5, 6, 8, 9, 11, 13, 17, X, and Y. Genetic factors that influence the rate of weight change (within-strain weight difference at two ages) over the lifespan of BXD RIs were mapped to the markers D2Mit369 and D3Mit130 at the genome-wide p < 0.05 for TA muscle in males (between 200 and 800 days) and females (between 500 and 800 days), respectively. Analysis of all age groups supported previous findings that the genetic effects may be muscle-, age-, and sex-specific.