Sort­ing out mus­cle dis­or­ders

Re­searchers have made great strides in un­der­stand­ing the var­i­ous forms of ty­ing up and how best to help sus­cep­ti­ble horses.

EQUUS - - Equus - By Chris­tine Barakat

Re­searchers have made great strides in un­der­stand­ing the var­i­ous forms of ty­ing up and how best to help sus­cep­ti­ble horses.

Aclas­sic case of ty­ing up is pretty dra­matic. The af­fected horse will hardly move as the large mus­cles of his hindquar­ters cramp into a solid, rock-hard mass. He is in ob­vi­ous pain, shak­ing and sweat­ing pro­fusely. You’ll know some­thing is wrong right away and have clear in­di­ca­tions that the prob­lem in­volves his mus­cles.

More of­ten, how­ever, equine mus­cle dis­or­ders pro­duce vague

and shift­ing signs that are easy to over­look or mis­in­ter­pret. A horse may sim­ply seem slightly stiff af­ter a day off, for ex­am­ple, or un­ac­count­ably lose sup­ple­ness. Or he may sud­denly be re­sis­tant to work. As a re­sult, many horses with chronic mus­cle dis­ease go through life with­out ac­cu­rate di­ag­no­sis or treat­ment.

One per­son hop­ing to change that is Stephanie Val­berg, DVM, PhD. Di­rec­tor of the Equine Neu­ro­mus­cu­lar Di­ag­nos­tic Lab­o­ra­tory at Michi­gan State Uni­ver­sity, Val­berg has spent her ca­reer iden­ti­fy­ing the var­i­ous mus­cle dis­or­ders that af­fect horses and help­ing own­ers and vet­eri­nar­i­ans rec­og­nize and man­age them.

That’s no small task. Even equine mus­cle prob­lems that arise from dif­fer­ent causes of­ten look sim­i­lar and can be dif­fi­cult to cat­e­go­rize.

“‘Ty­ing up’ is an um­brella term now, just like the word ‘colic’ is a gen­er­al­ized de­scrip­tion of a va­ri­ety of con­di­tions,” ex­plains Val­berg. “Ty­ing up can be a one-off event caused by a

con­flu­ence of fac­tors plus bad luck. When a horse re­peat­edly shows signs of ty­ing up, how­ever, that is clas­si­fied as chronic ex­er­tional rhab­domy­ol­y­sis (ER) and it’s much more likely there’s an on­go­ing phys­i­o­log­i­cal, and even ge­netic, cause.”

Work­ing with a team of tal­ented sci­en­tists, Val­berg has de­vel­oped bet­ter and more pre­cise meth­ods of di­ag­no­sis for equine my­opathies. Her work has also led to the de­vel­op­ment of man­age­ment pro­to­cols that can keep af­fected horses healthy and ac­tive, even at the high­est lev­els of com­pe­ti­tion.

THE BREAK­THROUGH: PSSM TYPE 1

One of Val­berg’s first mile­stones came in 1992 when she iden­ti­fied polysac­cha­ride stor­age my­opa­thy (PSSM), a con­di­tion char­ac­ter­ized by an in­abil­ity of a horse’s body to prop­erly store and uti­lize glyco­gen for en­ergy dur­ing pe­ri­ods of ex­er­cise. Her ini­tial work fo­cused on ab­nor­mal find­ings in mus­cle biop­sies taken from a sub­set of horses prone to chronic ER.

Orig­i­nally, PSSM was di­ag­nosed only through mus­cle biopsy. Pathol­o­gists would stain the sam­ples to iden­tify the type and lev­els of ac­cu­mu­lated glyco­gen. “In nor­mal horses, su­gar is stored in skele­tal mus­cle in the form of a highly branched poly­mer called glyco­gen, which is sen­si­tive to di­ges­tion by the sali­vary and pan­cre­atic en­zyme amy­lase,” says Val­berg. Nor­mal horses can read­ily break down glyco­gen to fuel mus­cles as it is needed, but Val­berg rec­og­nized that horses with PSSM store su­gar as an ab­nor­mal amy­lasere­sis­tant polysac­cha­ride that can­not be eas­ily uti­lized. By 2008, Val­berg and her team dis­cov­ered there was a ge­netic mu­ta­tion in a gene known as GYS1 in horses with amy­lase-re­sis­tant

polysac­cha­ride. Now a ge­netic test can iden­tify a horse with this form of PSSM be­fore he shows clin­i­cal signs. Val­berg called this form PSSM type 1 (PSSM1).

While the ex­act phys­i­o­log­i­cal mech­a­nism at work in PSSM1 is com­plex, the up­shot is that the ac­cu­mu­la­tion of ex­cess and/or ab­nor­mal glyco­gen dis­turbs the nor­mal pat­terns of en­ergy me­tab­o­lism dur­ing ex­er­cise, leav­ing the horse with an en­ergy deficit in the mus­cle cells that leads to mild to mod­er­ate cramp­ing, re­sis­tance to work and some­times full-blown ty­ing up. These signs are most of­ten seen in horses when they re­turn to work af­ter a lay-up pe­riod, about 10 to 20 min­utes into a ride.

“This ge­netic de­fect with PSSM1 orig­i­nated thou­sands

A ge­netic test can iden­tify a horse with PSSM type 1 be­fore he shows clin­i­cal signs.

of years ago and was in­cor­po­rated into light horse breeds at the time,” says Val­berg. “Our best the­ory is that when some heav­ier Euro­pean draft horses, par­tic­u­larly Bel­gian drafts, were crossed with lighter breeds to cre­ate a horse that could carry men in ar­mor breeders un­know­ingly in­cluded horses with PSSM1. At that time, be­fore the era of im­proved pas­tures and con­cen­trates, the abil­ity to store an ex­tra amount of en­ergy in your mus­cles was a good thing. These horses were work­ing eight-hour days, ev­ery day, and would uti­lize much of that glyco­gen.” In the mod­ern horse, though, that mu­ta­tion be­comes prob­lem­atic.

“In the mod­ern breeds, you see PSSM1 in the Quar­ter Horses, Paints, Ap­paloosas and, to a lesser ex­tent, the Mor­gan, Ten­nessee Walk­ing Horse and Rocky Moun­tain Spot­ted Sad­dle horses,” says Val­berg. “You’ll also see it in some horses with draft blood, like the Bel­gian, Percheron and Haflingers. We see it in warm­bloods at a lower fre­quency and don’t see it at all in Thor­ough­breds, Ara­bi­ans or Stan­dard­breds.”

The ef­fects of PSSM1 vary by breed. “In Quar­ter Horses, the pri­mary com­plaint is ty­ing up,” says Val­berg.

The com­bi­na­tion of a low-starch diet and con­sis­tent ex­er­cise works well in Quar­ter Horses with PSSM types 1 and 2 with up to 90 per­cent hav­ing no more episodes of ty­ing up.

“That’s the dra­matic, very ap­par­ent cramp­ing of the large mus­cle groups and mus­cle cell dam­age. In some draft horses, PSSM1 can be asymp­to­matic.”

SAME EF­FECT, DIF­FER­ENT CAUSES: PSSM TYPE 2 AND MFM

While work­ing to de­velop the ge­netic test for PSSM, Val­berg made a sur­pris­ing dis­cov­ery. “We had lit­er­ally hun­dreds of biopsy sam­ples from horses with clin­i­cal signs of PSSM and ab­nor­mal glyco­gen ac­cu­mu­la­tions in their mus­cle cells,” she says. “Once we were able to test for the mu­ta­tion, we went back and tested all those sam­ples. Only 72 per­cent of Quar­ter Horses di­ag­nosed with PSSM by mus­cle biopsy had the ge­netic mu­ta­tion. And in warm­bloods, we found the mu­ta­tion in only 8 per­cent of horses di­ag­nosed with PSSM by mus­cle biopsy. That told us that all cases of PSSM didn’t have the same un­der­ly­ing cause and it might not even be the same dis­ease process.” Val­berg be­gan clas­si­fy­ing these horses ---whose biop­sies showed ab­nor­mal glyco­gen ac­cu­mu­la­tions but who did not carry the ge­netic de­fect---as hav­ing PSSM type 2 (PSSM2).

“The pri­mary dif­fer­ence, from a prac­ti­cal stand­point, be­tween PSSM type 1 and type 2 is that one can be tested for ge­net­i­cally and the other can­not,” she says. “You might be able to find ge­netic vari­ants be­tween the horses, but there isn’t a sci­en­tif­i­cally ver­i­fied test for a mu­ta­tion that is clearly linked to the clas­sic mus­cle biopsy find­ings associated with PSSM type 2 horses.”

Val­berg es­ti­mates that ap­prox­i­mately 20 per­cent of Quar­ter Horses and 80 per­cent of warm­bloods with PSSM have type 2. That is not to say that 20 per­cent of all Quar­ter Horses have type 2 PSSM, she says, rather it means that 20 per­cent of those horses with mus­cle biop­sies show­ing ab­nor­mal glyco­gen stain­ing have PSSM2. Un­like type 1, type 2 has been found in other light breeds, such as Ara­bi­ans, Stan­dard­breds and Thor­ough­breds.

PSSM type 2 isn’t fully un­der­stood, but a key dif­fer­ence from PSSM type 1 might be the amount of glyco­gen stored in cells. Horses with type 1 have higher lev­els of glyco­gen (stored glu­cose) in their mus­cle cells, in ad­di­tion to ab­nor­mal amy­lase-re­sis­tant clump­ing. There ap­pear to be breed dif­fer­ences with PSSM2: Re­cent find­ings show that Quar­ter Horses with PSSM2 have high mus­cle glyco­gen, but warm­bloods and

From a prac­ti­cal stand­point, the pri­mary dif­fer­ence be­tween the two types of PSSM is that you can do a ge­netic test for type 1 but not for type 2.

Ara­bi­ans with type 2 do not ap­pear to store ex­ces­sive amounts of glu­cose.

“This is where our re­search is cur­rently fo­cused. The glyco­gen looks ab­nor­mal un­der the mi­cro­scope in both types of PSSM, but our breed-spe­cific find­ings sug­gest that this means there are dif­fer­ent causes in dif­fer­ent breeds. We are mea­sur­ing the amount of glyco­gen bio­chem­i­cally, and that in­for­ma­tion may even­tu­ally lead us to a bet­ter un­der­stand­ing of the dif­fer­ence be­tween forms of PSSM.”

To fur­ther ex­plore these dif­fer­ences Val­berg de­vel­oped new stains to eval­u­ate mus­cle with PSSM2. She found that Ara­bi­ans and warm­bloods pre­vi­ously di­ag­nosed with PSSM2 ac­tu­ally have clump­ing of glyco­gen that forms in breaks in the mus­cle’s con­trac­tile pro­teins. “We have found a pro­tein that is ab­nor­mal called desmin. Desmin’s job is to cre­ate an or­derly align­ment of the con­trac­tile pro­teins in the mus­cle cells,” says Val­berg. “With a new stain for desmin, mus­cle biop­sies could be re­spon­si­ble for the clin­i­cal signs of mus­cle pain and re­luc­tance to want to go for­ward or col­lect that we see in cer­tain PSSM2 horses.”

Termed my­ofib­ril­lar my­opa­thy (MFM), this con­di­tion is de­fined by clump­ing of desmin in spe­cific ar­eas of the mus­cle cells. (Val­berg notes that this con­di­tion is dif­fer­ent than MFM in peo­ple, and re­ly­ing on hu­man lit­er­a­ture for in­for­ma­tion is un­wise.) Eval­u­at­ing a biopsy to de­tect MFM can be tricky be­cause the horse’s age and the han­dling of the sam­ple can pro­duce false pos­i­tive or neg­a­tive re­sults. Val­berg sus­pects there is a ge­netic com­po­nent to MFM, but no sci­en­tif­i­cally val­i­dated ge­netic test for the con­di­tion is avail­able yet. “We find ge­netic vari­ants ex­ist be­tween MFM and healthy horses, but there has not been one spe­cific vari­ant that is present in all MFM horses and ab­sent in con­trols in our re­search,” Val­berg says.

CHAL­LENGES OF DI­AG­NO­SIS

Val­berg stresses that not ev­ery sore, re­sis­tant horse has a mus­cle dis­or­der or my­opa­thy. In fact, most don’t. “There are a mil­lion things that can make a horse mus­cle sore,” she says. “It’s not al­ways, or even usu­ally, mus­cle dis­ease.”

The di­ag­nos­tic process be­gins with an in­ves­ti­ga­tion of the more com­mon causes of sore­ness and re­luc­tance to ex­er­cise, Val­berg ex­plains. “You have to look at sad­dle fit, pos­si­ble train­ing is­sues, whether or not it’s a me­chan­i­cal lame­ness or sacroil­iac dis­ease. These are all di­ag­nos­tics that your ve­teri­nar­ian can do. The prob­lem is this can be ex­pen­sive, so many peo­ple are re­luc­tant to go through that whole process. But it’s the only way to find those much more com­mon causes.”

Your ve­teri­nar­ian will start by tak­ing a blood sam­ple to mea­sure mus­cle en­zymes. “If those are el­e­vated,

The ac­cu­mu­la­tion of ex­cess glyco­gen in mus­cles dis­turbs en­ergy me­tab­o­lism dur­ing ex­er­cise, which can lead to cramp­ing, re­sis­tance to work and full-blown ty­ing up.

no point in go­ing that route be­cause they just don’t have it. If you have a warm­blood, the like­li­hood of PSSM type 1 is small, but it’s a place to start and if the ge­netic test comes back pos­i­tive, you’ve found your prob­lem with­out hav­ing to take a biopsy.” In Quar­ter Horses there is an­other form of ex­er­tional rhab­domy­ol­y­sis, called ma­lig­nant hy­per­ther­mia, that can be di­ag­nosed by a ge­netic test. Horses with this form of ty­ing up of­ten have an in­creased body tem­per­a­ture when they have mus­cle cramp­ing and they can de­velop se­vere mus­cle dam­age.

If the ge­netic test comes back neg­a­tive, Val­berg then con­sid­ers the horse’s clin­i­cal signs, breed and even tem­per­a­ment to de­ter­mine what is the most likely cause of the on­go­ing prob­lem. “One dis­or­der, that we call re­cur­rent rhab­domy­ol­y­sis (RER) is found mainly in Thor­ough­breds and Stan­dard­breds who are very suc­cess­ful when they aren’t ty­ing up, but also tend to be very re­ac­tive and with a ner­vous tem­per­a­ment. It oc­curs when they are be­ing held back at a gal­lop or jig­ging. If the horse is ty­ing up af­ter a sit­u­a­tion like that, he likely has RER.”

For a horse who fre­quently ties up but doesn’t fit the pro­file for RER and tests neg­a­tive for PSSM1, the next step is a mus­cle biopsy. “When we look at a tis­sue sam­ple un­der the mi­cro­scope, we are look­ing at the size and shape of the cells, ev­i­dence of de­gen­er­a­tion and re­gen­er­a­tion, the amount of glyco­gen stored in them as well as clump­ing of glyco­gen and desmin,” says Val­berg. “From all of that, we will di­ag­nose a sub­set of these horses with PSSM type 2 or my­ofib­ril­lar my­opa­thy.”

Val­berg stresses that, ab­sent a ge­netic test, di­ag­nos­ing PSSM2 re­mains a bit sub­jec­tive: “You can’t base the di­ag­no­sis on the mus­cle biopsy alone. The biopsy is not spe­cific

Not ev­ery sore, re­sis­tant horse has a mus­cle dis­or­der or my­opa­thy. In fact, most don’t.

enough to use as a tool for pre­pur­chase ex­ams or mak­ing breed­ing de­ci­sions. Mus­cle biopsy is most ac­cu­rate when it is used in horses that have a high sus­pi­cion of dis­ease based on their clin­i­cal signs.”

TWO-STEP MAN­AGE­MENT

As tricky as my­opa­thy di­ag­nos­tics can be, the treat­ments are re­mark­ably straight­for­ward. In fact, for PSSM1 and PSSM2 in Quar­ter Horses where the prob­lem is too much glyco­gen, the man­age­ment rec­om­men­da­tions are iden­ti­cal.

The first step is a change in diet. Feed­stuffs that are high in su­gar and starch, such as corn, wheat, oats, bar­ley and mo­lasses, ap­pear to ex­ac­er­bate PSSM1 and PSSM2 in Quar­ter Horses. “Get­ting these horses onto a low-su­gar/ low-starch diet is key,” says Val­berg. “That might mean re­strict­ing graz­ing if the pas­tures are high in su­gar. We re­place the en­ergy of starch and su­gar with fat in the diet and this im­proves the horses’ ex­er­cise tol­er­ance.”

The sec­ond man­age­ment step is faith­ful daily ex­er­cise, which en­hances glu­cose uti­liza­tion and im­proves en­ergy me­tab­o­lism in skele­tal mus­cles. The horse doesn’t need to work hard, Val­berg stresses, but he does need some or­ga­nized ex­er­cise ev­ery sin­gle day. “Turnout in a pas­ture isn’t enough be­cause some horses just stand around,” she says. “You need to get on these horses and ride them or hand­walk them or longe them. Even if it’s only a bit of trot­ting for a few min­utes. That can make all the dif­fer­ence.”

The com­bi­na­tion of diet and ex­er­cise works well in Quar­ter Horses---up to 90 per­cent have no more episodes of ty­ing up---but Val­berg says warm­bloods may not re­spond to the same de­gree: “The fact that [treat­ments] don’t work as well in some breeds as oth­ers speaks to the dif­fer­ent un­der­ly­ing fac­tors that we don’t fully un­der­stand. But those rec­om­men­da­tions were the best we had at that point for all horses, and if you’ve ruled out ev­ery­thing else, it’s worth try­ing.”

Di­etary changes of low starch and su­gar don’t seem to be as cru­cial in horses with MFM, but Val­berg still rec­om­mends a diet that is mod­er­ate in sug­ars and starches: “Many feed com­pa­nies have now de­vel­oped sup­ple­ments of high-qual­ity amino

acids and we now rec­om­mend these sup­ple­ments for warm­bloods and Ara­bian horses with PSSM2 or MFM.”

Val­berg hopes, through re­search, to de­ter­mine if this type of diet op­ti­mizes turnover of struc­tural pro­teins in the mus­cle and builds mus­cle strength. “We are also work­ing on sup­ple­ments to en­hance en­ergy gen­er­a­tion and an­tiox­i­dant func­tion,” she says.

Mean­while, ex­er­cise rec­om­men­da­tions for horses with MFM are a bit more spe­cific than for those with ei­ther type of PSSM. Val­berg has found that MFM horses seem to re­spond best to work that ini­tially en­cour­ages them to stretch their topline, in a “long and low” frame for about five to 15 min­utes each day be­fore be­ing asked to do more col­lected work. And bring­ing an MFM horse back from a lay off needs to be done grad­u­ally, with a least two weeks of walk­ing, fol­lowed by at least two weeks of trot­ting be­fore the horse can­ters. In­ter­vals of walk and trot are rec­om­mended.

Re­search into my­opathies con­tin­ues. “With each new thing we learn, we re­al­ize how much we still don’t know,” Val­berg says, “but we’ve come such a long way al­ready.” Even though there are much more com­mon causes of mild to mod­er­ate mus­cle sore­ness in horses, be­ing able to ac­cu­rately iden­tify and suc­cess­fully man­age the rel­a­tive few who have these con­di­tions can mean the world of dif­fer­ence to those horses and their own­ers.

Dis­clo­sure state­ment: Stephanie Val­berg, DVM, PhD, and her col­leagues li­cense the PSSM1 test and re­ceive roy­al­ties. This con­flict is man­aged by Michi­gan State Uni­ver­sity, East Lans­ing, Michi­gan.

A cross sec­tion of mus­cle fibers from a biopsy of a horse with PSSM type 2 shows ab­nor­mal ag­gre­ga­tions of mus­cle glyco­gen.

Nor­mal horses can read­ily break down glyco­gen to fuel mus­cles as it is needed. In con­trast, horses with PSSM store su­gar as an ab­nor­mal polysac­cha­ride that can­not be eas­ily uti­lized.

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