Wimbledon finalist Milos Raonic was shocked at the US Open, with the tennis pro eliminated in the second round.
The fifth seed Canadian struggled physically against Ryan Harrison as the 120th seed American qualifier won 6-7 (4-7) 7-5 7-5 6-1.
Milos was among the favorites to win the Slam, after reaching the semifinals of the Australian Open and the final of the Wimbledon, losing to Murray on both occasions.
However, the 25-year-old struggled to carry his bags by the time he left the court following defeat by Harrison.
“It was probably just nerves and stress, a mental sort of over-exuberance,” Raonic said.
“Cramping in the left arm, right forearm there towards the end of the third set, both quads, a little bit in the hip flexor on the left. It was just catching me all over.
“I couldn’t switch grips from one point to the next. There were a few points where I would hold the racquet with my left hand and trying to stretch out my right hand in between shots, and that’s not going to work.”
Top seed Novak Djokovic reached round three without hitting a ball as Jiri Vesely withdrew before their match.
The Czech, 23, said he was “very, very disappointed” to pull out with inflammation of his left forearm.
Defending champion Djokovic, who has been struggling with a wrist injury, gets three days off before facing Russia’s Mikhail Youzhny on Friday.
Former champion Marin Cilic and French seeds Gael Monfils and Jo-Wilfried Tsonga progressed, with fourth seed Rafael Nadal to play Italy’s Andreas Seppi later on Wednesday.