"Long before it's in the papers"
August 03, 2010

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To keep muscles strong, “garbage” must go

Dec. 3, 2009
Courtesy Cell Press
and World Science staff

To main­tain mus­cle strength with age, cells must get rid of gar­bage that slowly ac­cu­mu­lates in them, just as a house­hold does, ac­cord­ing to a new stu­dy. 

The cel­lu­lar junk in­cludes tox­ic clumps of mal­formed pro­teins, pathogens and spent or­ganelles, which are cel­lu­lar com­part­ments used for spe­cif­ic func­tions.

The re­search­ers stud­ied mice de­fi­cient for a gene re­quired for the tightly con­trolled pro­cess of de­grada­t­ion and re­cy­cling with­in cells known as au­tophagy. The ro­dents showed pro­found mus­cle shrink­age and weak­en­ing that wors­ened with age.

“If there is a fail­ure of the sys­tem to re­move what is dam­aged, and that per­sists, the mus­cle fi­ber is­n’t hap­py,” said Mar­co San­dri of the Un­ivers­ity of Pa­do­va in It­a­ly. The re­search by Sand­ri and col­leagues ap­pears in the De­cem­ber is­sue of the jour­nal Cell Me­tab­o­lism.

The mus­cle wast­ing in mice seems to bear some re­sem­blance to cer­tain forms of mus­cle-wast­ing dis­eases, San­dri said. He now sus­pects that this kind of mech­an­ism may of­fer in­sight in­to some of those still-unexplained con­di­tions, as well as the mus­cle weak­en­ing that comes with nor­mal ag­ing.

Re­search­ers knew be­fore that ex­ces­sive au­tophagy could al­so lead to mus­cle loss and dis­ease. The new find­ings high­light the im­por­tance of main­taining a nor­mal lev­el of au­tophagy. Al­though that seems to make sense in ret­ro­spect, San­dri said, it was­n’t what his team had in­i­tially ex­pected.

“We thought if you re­duced au­tophagy it might pro­tect against” mus­cle shrink­age, he said. “In­stead, it’s the op­po­site. We real­ized, OK, of course, if you don’t re­move the dam­age, it trig­gers weak­ness.”

The find­ings may have clin­i­cal im­plica­t­ions, he said. There has been in­ter­est in de­vel­op­ing ther­a­pies to block pro­teins’ de­grada­t­ion for treat­ing cer­tain mus­cle-wast­ing dis­or­ders. But in some cases, at least, “it may be bet­ter to ac­ti­vate au­tophagy and re­move the gar­bage in the cells,” San­dri said. The re­search­ers think si­m­i­lar treat­ments might com­bat mus­cle weak­ness with ag­ing as well, not­ing that an­oth­er study has shown a de­cline in the ef­fi­cien­cy of au­tophagy with age.

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To maintain muscle strength with age, cells must get rid of garbage that slowly accumulates in them, just as a household does, according to a new study. The cellular junk includes toxic clumps of misformed proteins, pathogens and spent organelles, which are cellular compartments used for specific functions. The researchers studied mice deficient for a gene required for the tightly controlled process of degradation and recycling within cells known as autophagy. The rodents showed profound muscle shrinkage and weakening that worsened with age. “If there is a failure of the system to remove what is damaged, and that persists, the muscle fiber isn’t happy,” said Marco Sandri of the University of Padova in Italy. The research appears in the December issue of the journal Cell Metabolism The muscle wasting in mice seems to bear some resemblance to certain forms of muscle-wasting diseases, Sandri said. He now suspects that this kind of mechanism may offer insight into some of those still-unexplained conditions, as well as the muscle weakening that comes with normal aging. Researchers knew before that excessive autophagy could also lead to muscle loss and disease. The new findings highlight the importance of maintaining a normal level of autophagy to clear away the debris and keep muscles working properly. Although the discovery seems to make perfect sense in retrospect, it wasn’t what Sandri’s team had initially anticipated. “We thought if you reduced autophagy it might protect against atrophy,” he said. “Instead, it’s the opposite. We realized, OK, of course, if you don’t remove the damage, it triggers weakness.” The findings may have clinical implications, he said. There has been interest in developing therapies to block proteins’ degradation for treating certain muscle-wasting disorders. But in some cases, at least, “it may be better to activate autophagy and remove the garbage in the cells,” Sandri said. The researchers think similar treatments might combat muscle weakness with aging as well, noting that another study has shown a decline in the efficiency of autophagy during aging.