UNM Biologists Manipulate Muscle Identity in Fruit Flies

Did you ever won­der why some Olympic run­ners are so good at short dis­tances, while oth­ers excel at long-distance exer­cises? Much of this dif­fer­ence is accounted for by the types of mus­cle fibers that pre­dom­i­nate in the indi­vid­ual: fast fibers for sprint­ers, and slow fibers for endurance ath­letes. How the ratio of dif­fer­ent mus­cle fiber types is pre­de­ter­mined in the body has always been of inter­est to researchers.

Recently, sci­en­tists at the Uni­ver­sity of New Mex­ico, includ­ing Research Assis­tant Pro­fes­sor Anton Bryant­sev, and Pro­fes­sor and Biol­ogy Depart­ment Chair Richard Cripps, used fruit flies to dis­cover a mech­a­nism that con­verts one mus­cle type into another, and to alter the func­tion of the muscle.

The research, funded through a four-year, $800,000 grant from the National Insti­tutes of Health and titled “Extraden­ti­cle and Homoth­o­rax Con­trol Adult Mus­cle Fiber Iden­tity in Drosophila,” was pub­lished this week in the pres­ti­gious pub­li­ca­tion Devel­op­men­tal Cell.

Drosophila melanogaster, or fruit flies, have a long his­tory of genetic research that has helped unravel processes of human devel­op­ment, and has helped to pin­point var­i­ous genetic prob­lems. Bryant­sev and Cripps were able to manip­u­late mus­cle fiber iden­tity by using genes named Extraden­ti­cle and Homoth­o­rax to con­vert one mus­cle type into another. Their find­ings sug­gest that an evo­lu­tion­ar­ily con­served genetic path­way, also present in humans, deter­mines mus­cle fiber differentiation.

“Our research shows that two dif­fer­ent mus­cle types in fruit flies can be inter-converted, by chang­ing the expres­sion of two genes,” said Cripps. “We show these two genes are at the top of a hier­ar­chy of genes that con­trol mus­cle fiber fate.”

The sci­en­tists stud­ied for­ma­tion of two dra­mat­i­cally dif­fer­ent mus­cles in the fly body, flight and jump mus­cles. The two-year project first involved iden­ti­fy­ing and cloning DNA ele­ments that would report the proper devel­op­ment of each type of muscle.

“There are two mol­e­c­u­lar reporters we used,” said Bryant­sev. “One reporter tells if the flight mus­cle forms, and the other if the jump mus­cle forms.”

The con­structed reporters were then ana­lyzed under con­di­tions when var­i­ous mas­ter con­trol genes were exper­i­men­tally turned off, or knocked down. Fol­low­ing the analy­sis of over 70 gene knock­downs, Bryant­sev et al. found that selec­tive knock­down of Extraden­ti­cle or Homoth­o­rax caused the flight mus­cle reporter to be active at much lower lev­els, while the jump mus­cle reporter dra­mat­i­cally increased its activity.

“This sug­gested to us that the flight mus­cles were turn­ing into jump mus­cles.” Bryant­sev said. “When we looked inside the mutant flies, and saw that the mor­phol­ogy of the flight mus­cles was instead com­prised of more jump-like mus­cles, we couldn’t believe it. We did the tests again and again and still got the same result. We then did a crazy exper­i­ment, where we forced these two genes to be expressed in jump mus­cles, and it turned the jump mus­cle into a flight mus­cle. That was when we knew we had uncov­ered an impor­tant and basic mech­a­nism for con­trol­ling mus­cle fiber identity.”

“Mus­cle fibers are spe­cial­ized to per­form dif­fer­ent tasks in the body, and this research has iden­ti­fied key genes that con­trol this dif­fer­en­ti­a­tion process dur­ing fly devel­op­ment,” said Susan Haynes, Ph.D., of the National Insti­tutes of Health’s National Insti­tute of Gen­eral Med­ical Sci­ences, which par­tially funded the work. “Because these genes are also found in mam­mals, these find­ings may pro­vide impor­tant insights into human mus­cle per­for­mance and the under­ly­ing causes of cer­tain mus­cle diseases.”

Sev­eral UNM researchers, includ­ing grad­u­ate stu­dent TyAnna Lovato and research tech­ni­cian Sandy Duong, played impor­tant roles in the dis­cov­ery. The work also fea­tured a col­lab­o­ra­tion with Juli Uhl and Brian Gebelein from Cincin­nati Children’s Hospital.

“I helped with devel­op­ing the RNAi screen, gen­er­ated many of the trans­genic lines that were used, and car­ried out the in situ hybridiza­tion exper­i­ments.” said Lovato.

Duong per­formed the exten­sive screen­ing exper­i­ments that led to the dis­cov­ery of the two genes’ roles.

“I did a large por­tion of the RNAi screen as well as the sec­tion­ing and stain­ing of the sam­ples,” said Duong. “I helped TyAnna with the in situs and Tonya (Brunetti, another grad­u­ate stu­dent) on the bio­chem­i­cal assays, by pro­vid­ing the sections.”

The research also fea­tures con­tri­bu­tions from Biol­ogy under­grad­u­ate majors, who spent long hours between classes in the research lab­o­ra­tory. Co-author and under­grad­u­ate stu­dent Cloyce Nel­son said the research was one of the most excit­ing expe­ri­ences she had as an undergraduate.

“Through this expe­ri­ence I was able to fully immerse myself in my major, as well as learn many aspects about being a biol­o­gist that are not taught in the class­room,” said Nel­son. “I was able to work on the begin­ning stages of this project, and it was an honor to assist many tal­ented peo­ple to bring it to com­ple­tion. See­ing our research pub­lished has demon­strated how my work can have a broader impact on sci­en­tific advance­ments. This has inspired me, and given me con­fi­dence that my aca­d­e­mic efforts can lead to real world results.”

While we won’t be see­ing fruit flies at the Olympics any time soon, the results of the research could play a key role in ongo­ing stud­ies involv­ing mam­mals. The same genes used in the Drosophila research are also found in humans.

Media con­tact: Steve Carr (505) 277‑1821; email: scarr@unm.edu