"Long before it's in the papers"
January 27, 2015


Scientists said to restore some youthful strength to old mice

Feb. 17, 2014
Courtesy of Stan­ford Uni­vers­ity School of Med­i­cine
and World Science staff

Sci­en­tists have an­nounced that they were able to re­store the strength of some mus­cles in old mice to youth­ful lev­els, through a treat­ment ap­plied to mus­cle cells.

The treat­ment—which re­search­ers hope to even­tu­ally try on peo­ple—in­volved re­mov­ing mus­cle stem cells from the mice, treat­ing them and put­ting them back in­side the ro­dents.

“Two months af­ter trans­planta­t­ion, these mus­cles ex­hib­ited forc­es equiv­a­lent to young, un­in­jured mus­cles,” said Post­doc­tor­al schol­ar Ben­ja­min Cos­grove of Stan­ford Uni­vers­ity School of Med­i­cine in Cal­i­for­nia, one of the re­search­ers.

The in­ves­ti­ga­tors found that over time, stem cells, or im­ma­ture cells, in mus­cle tis­sues ded­i­cat­ed to re­pair­ing dam­age be­come less able to gen­er­ate new mus­cle fibers and strug­gle to self-renew.

“In the past, it’s been thought that mus­cle stem cells them­selves don’t change with age, and that any loss of func­tion is pri­marily due to ex­ter­nal fac­tors in the cells’ en­vi­ron­ment,” said Hel­en Blau, a Stan­ford mi­cro­bi­ol­o­gist. But “when we iso­lat­ed stem cells from old­er mice, we found that they ex­hib­it pro­found changes with age,” two thirds of them being “dys­func­tional,” said Blau. She is sen­ior au­thor of a re­port on the find­ings pub­lished on­line Feb. 16 in the jour­nal Na­ture Med­i­cine.

The sci­en­tists found that many mus­cle stem cells from mice that were two years old, equiv­a­lent to about 80 years of hu­man life, showed high lev­els of ac­ti­vity in a chem­i­cal pro­cess called the p38 MAP ki­nase path­way. This ham­pers the pro­lifera­t­ion of the stem cells and en­cour­ages them to in­stead be­come an­oth­er type of mus­cle pro­gen­i­tor cell that pro­liferates less.

Us­ing a drug to block this chem­i­cal path­way in old stem cells, while al­so grow­ing them on a soft sub­stance called hy­dro­gel, al­lowed them to di­vide rap­idly and make many po­tent new stem cells that can ro­bustly re­pair mus­cle dam­age, Blau said.

The treat­ment “s­tim­u­lates stem cells from old mus­cle tis­sues that are still func­tional to beg­in di­vid­ing and self-renew,” she ex­plained. When trans­planted back, the treated stem cells mi­grate to their nat­u­ral places and pro­vide a long-lasting stem cell re­serve to con­trib­ute to re­peat­ed de­mands for mus­cle re­pair, she added.

“We can take cells from an old an­i­mal, treat them for sev­en days—dur­ing which time their num­bers ex­pand dra­mat­ic­ally, as much as 60-fold—and then re­turn them to in­jured mus­cles in old an­i­mals to fa­cil­i­tate their re­pair,” Blau said.

The pro­cess de­pended on use of the hy­dro­gel; grow­ing cells on the stand­ard, hard plas­tic lab plates did­n’t work, the sci­en­tists added, probably be­cause the soft hy­dro­gel is more like the cells’ nat­u­ral en­vi­ron­ment.

The re­search­ers tested the abil­ity of the re­ju­ve­nat­ed stem cells to re­pair mus­cle in­ju­ry and re­store strength in old mice. “We were able to show that trans­planta­t­ion of the old treated mus­cle stem cell popula­t­ion re­paired the dam­age and re­stored strength to in­jured mus­cles of old mice,” Cos­grove said.

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Scientists have announced that they were able to restore some muscle strength in old mice to youthful levels, through a treatment applied to muscle cells. The treatment—which researchers hope to eventually try on people—involved removing muscle stem cells from the mice, treating them and putting them back inside the rodents. “Two months after transplantation, these muscles exhibited forces equivalent to young, uninjured muscles,” said Postdoctoral scholar Benjamin Cosgrove of Stanford University School of Medicine in California, one of the researchers. The investigators found that over time, stem cells, or immature cells, in muscle tissues dedicated to repairing damage become less able to generate new muscle fibers and struggle to self-renew. “In the past, it’s been thought that muscle stem cells themselves don’t change with age, and that any loss of function is primarily due to external factors in the cells’ environment,” said Helen Blau, a Stanford microbiologist on the project. But “when we isolated stem cells from older mice, we found that they exhibit profound changes with age… two-thirds of the cells are dysfunctional when compared to those from younger mice,” said Blau, senior author of a report on the findings published online Feb. 16 in the journal Nature Medicine. The scientists found that many muscle stem cells from mice that were two years old, equivalent to about 80 years of human life, showed high levels of activity in a chemical process called the p38 MAP kinase pathway. This hampers the proliferation of the stem cells and encourages them to instead become another type of muscle progenitor cell that proliferates less. Using a drug to block this chemical pathway in old stem cells, while also growing them on a soft substance called hydrogel, allowed them to divide rapidly and make a large number of potent new stem cells that can robustly repair muscle damage, Blau said. The treatment “stimulates stem cells from old muscle tissues that are still functional to begin dividing and self-renew,” she explained. When transplanted back, the treated stem cells migrate to their natural places and provide a long-lasting stem cell reserve to contribute to repeated demands for muscle repair, she added. “We can take cells from an old animal, treat them for seven days — during which time their numbers expand dramatically, as much as 60-fold — and then return them to injured muscles in old animals to facilitate their repair,” Blau said. The process depended on use of the hydrogel—growing cells on the standard, hard plastic plates didn’t work, the scientists added, probably because the soft hydrogel is more like the cells’ natural environment. The researchers tested the ability of the rejuvenated old muscle stem cell population to repair muscle injury and restore strength in two-year-old mice. “We were able to show that transplantation of the old treated muscle stem cell population repaired the damage and restored strength to injured muscles of old mice,” Cosgrove said.