Alexander Zverev admitted he was "annoyed" at having to defend his status as world No. 1 after suffering an opening-round defeat at the Paris Masters, while 24-time Grand Slam champion Novak Djokovic also crashed out on a day of major upsets Wednesday.
Carlos Alcaraz, however, avoided an early exit, overcoming Alex Michelsen 7-6 (7/4), 6-3 to begin his campaign with a straight-sets victory.
Zverev, 29, had long been regarded as one of tennis' biggest underachievers at the Grand Slam level before finally breaking through this year with victories at the French Open and U.S. Open.
Those triumphs propelled the German to the top of the ATP rankings for the first time in his career earlier this month.
But his first tournament as world No. 1 ended in disappointment as Italy's Lorenzo Musetti, ranked 24th, claimed a 7-6 (7/5), 6-2 victory to advance to the third round.
"Stress, I don't know if stress. I was a bit annoyed, to be honest," Zverev told reporters.
"I feel like I'm the only world number one in tennis history that has to explain why it's OK for me to be world number one, which I find quite difficult, because I think I deserve to be where I am, even though I lost today."
After taking a commanding position in the first-set tiebreaker, Zverev made a series of errors, losing five consecutive points before dropping six of the next eight games to crash out in the first round.
"I said even before playing with him that today was going to be the best challenge and the toughest challenge that this sport can give me. So I'm really happy that I took my chances today," Musetti, a former world No. 5, said.
Djokovic saw his hopes of winning a record-extending eighth Paris Masters title and qualifying for the ATP Finals disappear as he lost 2-6, 6-3, 6-3 to world No. 83 Rinky Hijikata.
After cruising through the first set, the 39-year-old found himself in a battle against the Australian qualifier.
Hijikata broke Djokovic in the eighth game of the second set before serving out to force a decider.
The third set remained closely contested until the Serb was broken twice in succession to hand his 25-year-old opponent victory.
The defeat effectively brought Djokovic's season to an end, with the veteran telling reporters his plans for the coming weeks were "just rest."
Hijikata, the 2023 Australian Open men's doubles champion, will face Tomas Martin Etcheverry for a place in the quarterfinals after the Argentine defeated Australian eighth seed Alex de Minaur 7-6 (7/2), 6-3.
Former world No. 1 Daniil Medvedev joined the list of top-seed casualties as the fifth-ranked Russian lost in straight sets to Peru's Ignacio Buse.
Second seed Alcaraz bucked the trend with his victory over 35th-ranked American Michelsen in the night session.
"Really happy to get the win," Alcaraz said on court.
"It's been a really difficult day for the top guys, but I just try not to think about it and I try to step out there, play my best and enjoy," he later told reporters, avoiding a repeat of his own opening-round defeat in the French capital last year.
Both players exchanged service breaks midway through the first set as the opener headed toward a tiebreaker.
Michelsen raced into a 4-1 lead in the tiebreaker before Alcaraz found his range with his forehand and won the next six points to take the set.
After a tightly contested second set, Alcaraz secured a crucial break in the eighth game before serving out the match to reach the last 16.
Elsewhere, seventh seed Frances Tiafoe also lost his opening match, falling 6-3, 1-6, 7-6 (11/9) to Quentin Halys.
The Frenchman's victory over the American was also good news for his compatriot Arthur Fils, who secured qualification for the ATP Finals.
Fils, ranked No. 7 in the world, is now assured of making his debut at the season-ending tournament, which runs Nov. 15-22 in Turin.
With qualification secured, the 22-year-old closed play Wednesday with a 6-3, 7-6 (7/4) victory over Czech qualifier Tomas Machac.
Ben Shelton will headline Thursday's day session when the third seed takes on home favorite Arthur Rinderknech for a place in the quarterfinals. Alcaraz will return in the night session to face Matteo Berrettini.