Haploinsufficiency of myostatin protects against aging‐related declines in muscle function and enhances the longevity of mice

Abstract

The molecular mechanisms behind aging-related declines in muscle function are not well understood, but the growth factor myostatin (MSTN) appears to play an important role in this process. Additionally, epidemiological studies have identified a positive correlation between skeletal muscle mass and longevity. Given the role of myostatin in regulating muscle size, and the correlation between muscle mass and longevity, we tested the hypotheses that the deficiency of myostatin would protect oldest-old mice (28–30 months old) from an aging-related loss in muscle size and contractility, and would extend the maximum lifespan of mice. We found that MSTN+/− and MSTN−/− mice were protected from aging-related declines in muscle mass and contractility. While no differences were detected between MSTN+/+ and MSTN−/− mice, MSTN+/− mice had an approximately 15% increase in maximal lifespan. These results suggest that targeting myostatin may protect against aging-related changes in skeletal muscle and contribute to enhanced longevity.

Biochemistry and Biology of GDF11 and Myostatin

“…Studies in mice also suggest that alterations of MSTN signaling may impact lifespan. A recent study of male MSTN +/+ , MSTN +/− and MSTN −/− mice (n=38-42 mice per group), revealed an increase in both median and maximum lifespan of heterozygous animals, which showed a 30% decrease in circulating MSTN levels, as compared to wild-type controls 99 . In contrast, the median and maximal lifespan of MSTN −/− mice did not differ from wild-type.…”

“…However, other experiments reveal that MSTN-null mice develop increased heart and body weights. MSTN −/− mice (28-30 month-old) were reported to have increased normalized heart mass at death compared to MSTN +/+ and MSTN +/− mice 99 . Aged mice with MSTN deletion have improved fractional shortening, smaller left ventricle diastolic diameters and less fibrosis compared to aged wild-type mice 100 .…”

“…Given observations reported previously for genetic manipulation of MSTN expression 88, 98, 99 , it is likely that administration of recombinant MSTN could achieve a similar anti-hypertrophic effect, but this has yet to be tested. Furthermore, it remains to be determined if a similar effect can be achieved with other ligands that likewise activate the SMAD2/3 pathway, such as members of the TGFβs or activin sub-classes.…”

Genetics of aging and longevity

“…У людей мышечная масса по-ложительно коррелирует с продолжительностью жизни, и быстрая потеря мышечной массы во время старения часто приводит к различным заболеваниям (Miller et al, 2002). Инактивация миостатина приводит к росту мы-шечной массы, и этот эффект может использоваться при борьбе с различными нарушениями, такими как миопатия (Hulmi et al, 2013), рак (Gallot et al, 2014) и старение (Mendias et al, 2015). Показано, что искусственное пода-вление активности миостатина у старых мышей положи-тельно сказывается на метаболизме и физических функ-циях (White, LeBrasseur, 2014).…”

“…Показано, что искусственное пода-вление активности миостатина у старых мышей положи-тельно сказывается на метаболизме и физических функ-циях (White, LeBrasseur, 2014). Крысы с 30 % снижением циркулирующего в крови миостатина имеют увеличенную продолжительность жизни (Mendias et al, 2015).…”