The former Cy Young Award winner allowed three earned runs on four innings pitched. The Astros drop the middle of three games with the Minnesota Twins, 4-1.
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Runs were hard to come by for the Astros, who came up with only seven hits to go 1-for-6 on runners in scoring position.
Jake Marisnick drove the only run on a two-out RBI that sent Josh Reddick home.
Keuchel's futility saw its apex in the second inning when he walked Joe Mauer on bases loaded to bring the game to 3-1.
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Of three starts in the season, Keuchel notched his second loss. Keuchel is next scheduled to start in Seattle on April 16.
Houston (9-3) will look to win the series on Wednesday with Lance McCullers Jr. taking the mound for a matinee game set for 12:10 p.m.