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Drug may trick body into “thinking” you worked out

July 31, 2008
Courtesy Cell Press
and World Science staff

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.

A study with mice suggests the exis­tence of drugs that trick the body into "be­liev­ing" it has exer­cised. (Im­age cour­tesy Salk In­sti­tute)


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.”

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While steroids can help build the muscle power that so often tempt 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 worries. 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. Earlier studies had found that a red wine ingredient called resveratrol could build endurance, but only at enormous doses and by uncertain means. Both chemicals tested in the new study work by specifically tapping into the molecular pathways that normally reprogram muscle genetics 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 100 percent greater running endurance as 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 trained mice given a placebo, they report. 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. 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.” Given the potential for abuse by athletes set on winning at any cost, 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.