quarta-feira, 19 de novembro de 2008

Drug may trick body into “thinking” you worked out

July 31, 2008

While steroids can give the boost in muscle pow­er that so of­ten tempts ath­letes to abuse these drugs, re­search­ers say there has­n’t been a tar­geted drug ca­pa­ble of build­ing the en­dur­ance needed to run a mar­a­thon or ride a bike through the Alps.

Now there might be, sug­gests a new study with mice. And that’s cre­at­ing both hope and worry.

The study found that a drug de­vel­oped for the treat­ment of met­a­bol­ic dis­ease, when tak­en in com­bina­t­ion with ex­er­cise, gives mice the abil­ity to run far­ther than ex­er­cise alone can. And an­oth­er chem­i­cal en­dowed mice with great­er en­dur­ance, even with­out the work­out.

“It’s trick­ing the mus­cle in­to ‘be­liev­ing’ it’s been ex­er­cised dai­ly,” said Ronald Ev­ans of the Salk In­sti­tute in La Jolla, Ca­lif. Both com­pounds “are very log­i­cal tar­gets for ath­let­ic abuse, and we need to be aware of that.” But for peo­ple with health prob­lems that pre­clude much ex­er­cise, the find­ings could be a boon, he added.

The study by Ev­ans and col­leagues ap­pears in the July 31 on­line is­sue of the re­search jour­nal Cell.

Ev­ans said his group has al­ready spo­ken to the World An­ti-Doping Agen­cy and is de­vel­op­ing a test aimed at de­tect­ing use of the PPARd-boost­ing drug. That test won’t be avail­a­ble in time for this sum­mer’s Olym­pic games, he said. It al­so would­n’t de­tect the use of AICAR, a chem­i­cal that is avail­a­ble but is­n’t an FDA-approved drug.

Ear­li­er stud­ies had found that a red wine in­gre­di­ent called res­ver­a­trol could build en­dur­ance, but only at enor­mous doses and by un­cer­tain means. The chem­i­cals tested in the new study are thought to work by spe­cif­ic­ally tap­ping in­to the mo­lec­u­lar me­ch­an­isms that nor­mally “re­pro­gram” mus­cle genes in re­sponse to ex­er­cise.

Ev­ans said it’s not cer­tain that ath­letes could get a boost from the drugs: the ef­fects in mice might not work as well in highly trained peo­ple who may be “push­ing the lim­its” al­ready.

Skele­tal mus­cle, the type of mus­cle that moves the body, comes in two main types: bulky, fast-twitch mus­cles for pow­er and speed and slen­der slow-twitch mus­cles for en­dur­ance. Fast-twitch mus­cles burn sug­ar that must be stored in the mus­cle it­self while slow-twitch mus­cle burns fat.

Ev­ans’ team had pre­vi­ously found they could ge­net­ic­ally en­gi­neer, or “pre-program” mice to pro­duce more of the fat-burning slow-twitch mus­cle fibers, turn­ing them in­to “mar­a­thon mice” with nearly twice the run­ning en­dur­ance of un­trained adults. The key was boost­ing the ac­ti­vity of a gene in mus­cle called PPARd, known to con­trol oth­er genes im­por­tant to skele­tal mus­cle me­tab­o­lism.

But could you re-program rath­er than pre-program mus­cles by simply giv­ing a drug that acts on PPARd? To find out, the re­search­ers gave mice an ex­pe­ri­men­tal drug, known only as GW1516, that in­creases PPARd ac­ti­vity. The drug is be­ing tested for the treat­ment of met­a­bol­ic dis­ease, but Ev­ans wanted to know its ef­fects on mus­cle. “It was a spec­tac­u­lar fail­ure,” he said. It “had no im­pact on run­ning abil­ity” even though there were changes in mus­cle gene ac­ti­vity.

Some­thing was mis­sing, so the sci­en­tists took a dif­fer­ent tack. They gave the PPARd drug to mice that were un­der­go­ing ex­er­cise train­ing. The same dose and dura­t­ion of GW1516 treat­ment that pre­vi­ously failed to al­ter per­for­mance, when paired with four weeks of ex­er­cise train­ing, in­creased the an­i­mals’ run­ning time by 68 per­cent and their run­ning dis­tance by 70 per­cent over other trained mice, the new study re­ports.

The mus­cles of those mice al­so showed a un­ique “en­dur­ance gene sig­na­ture,” in­clud­ing pat­terns of gene ac­ti­vity not seen with ei­ther the drug or ex­er­cise alone, ac­cord­ing to the in­vest­i­ga­tors. That pat­tern bore a strik­ing re­sem­blance to the one seen years ear­li­er in the ge­net­ic­ally en­gi­neered mar­a­thon mice, they not­ed.

Since PPARd on its own was­n’t enough, the re­search­ers de­cid­ed to try one more thing: a chem­i­cal known as AICAR that was known to act on a pro­tein in the body called AMPK. Ev­ans’ group sus­pected AMPK might be the link be­tween ex­er­cise and PPARd.

To their sur­prise, even in sed­en­tary mice, four weeks of AICAR treat­ment alone in­duced met­a­bol­ic genes and en­hanced run­ning en­dur­ance by 44 per­cent. “We were blown away that AICAR alone mim­icked ex­er­cise—not to the same lev­el but a healthy boost,” Ev­ans said.

“We re­vealed that syn­thet­ic PPARd ac­tiva­t­ion and ex­er­cise or more im­por­tantly AMPK ac­tiva­t­ion alone… re-programs the skele­tal mus­cle ge­nome and dra­mat­ic­ally en­hances en­dur­ance,” the re­search­ers wrote. “We be­lieve that the strat­e­gy of re-organizing the pre­set ge­net­ic im­print of mus­cle (as well as oth­er tis­sues) us­ing ex­er­cise mi­met­ic drugs has ther­a­peu­tic po­ten­tial in treat­ing cer­tain mus­cle dis­eases such as wast­ing and frail­ty as well as obes­ity where ex­er­cise is known to be ben­e­fi­cial.”

Source: http://www.world-science.net

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