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New CR Mice Study Suggests When to Exercise to Preserve Muscles

Dean Pomerleau

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Lose of muscle mass (sarcopenia) is a problem that humans other primates and rodents suffer as a result of aging. CR has long been known to attenuate this muscle loss, including in CR primates [2]. But on the other hand, CR animals and humans typically enter old age with less muscle to start with, so excessive muscle loss is still an issue for CR practitioners to be concerned about. 


This new study [1] posted by James Cain (thanks James!) found once again that CR prevented sarcopenia in mice, but as usual, the CR mice had less lean mass throughout most of their life. As a result of these competing influences, by the time the mice were quite old (28 months), the amount of muscle in the CR and control animals were similar, as was their strength:


Particularly at the age of 28 months, differences in muscle mass between the two intervention groups are relatively small, specifically when compared with the large difference present in body weight at all time points.



In contrast to mice that have received the control diet, in the caloric-restricted group, no age-related decline in muscle mass was observed, which could be interpreted as protecting against sarcopenia. Absolute muscle masses were approximately similar in both groups at 28 months of age as were grip strength measurements.


The CR mice also showed improved insulin sensitivity relative to controls (no surprise). They also had a lot less fat (also not surprising) but what was surprising was that the CR mice had higher bone mineral density at both 14 and 23 months, which is encouraging! Here is the BMD graph:




But perhaps the most interesting thing about the study is the author's discussion of why they think muscle mass may have been preserved. They talk about a bunch of biochemical and gene expression differences between aged CR and control mice that might have contributed to reduced sarcopenia in the CR group. But they also focus a lot on the role of activity (e.g. exercise) and its timing relative to eating in preserving muscle mass.


As you can see from this graph comparing daily activity of the control and CR animals at 12 months and 23 months, the controls were more active at 12 months than the CR group, but their activity declined precipitously. In contrast, the CR mice maintained, and perhaps even increased their activity between 12 and 23 months. So by 23 months the two groups had about the same level of daily activity:




And after 24 months of age, the control mice daily activity fell off a cliff, to the point where the total daily activity of the CR mice greatly exceeded that of the fat, sick control mice. Here is the graph daily activity of old (28 month) control and CR mice compared with young mice:




Maintaining a high level of activity likely helped the CR mice maintain their lean muscle mass (and strength) while the controls lost their muscles and strength. So this suggests the ability to remain active into old age as a result of staying lean and healthy on CR can help us maintain muscle mass relative to people eating a crappy, high caloric diet. 


The authors go on to hypothesize that increased exercise in the old CR group relative to the old controls may not be the only behavioral contributor to muscle preservation. They suggest that timing and intensity of the exercise may play a role as well. As is apparent in this graph of the timing of daily activity in young control, old control, and old CR mice, the old CR mice had a burst of high intensity exercise in the 2 hours prior to feeding, while the other two groups had exercise spread throughout the day (with the old controls having much less activity than the other two groups).




The authors suggest that this bout of intense exercise just prior to the bolus of food (protein) given at mealtime may have been especially beneficial for muscle building / maintenance relative to lower intensity exercise spread throughout the day as seen in the control animals. Here is how the authors (rather awkwardly) describe it:


Mice on a CR diet have more hunger and therefore show an increased [Food Anticipatory Activity]. This behaviour stays for the rest of their life if CR maintains. This activity is different from normal daily activity in a way that it is more intense: more running and climbing. The animals compensate for the activity [by being less active] during the rest of the day, which might result in a decreased total daily activity. Furthermore, it is hypothesized that the increase in activity just before the meal is provided, increases the insulin sensitivity of the body and assumedly of the muscle. A lower total provided load of carbs and fat due to the CR can further contribute to an improved insulin sensitivity. Next to that triggers the bout of activity an anabolic response of the skeletal muscles involved in this activity. We moreover speculate that the increased insulin sensitivity combined with the activity-induced anabolic response lower the threshold needed for protein synthesis and therefore make maintenance of muscle protein possible.


Here is their conclusion:


Control animals showed an age-dependent sarcopenia, while caloric-restricted animals showed muscle mass and strength maintenance during lifespan. An adequate amount of protein provided as a bolus, preferably in combination with exercise, is currently recommended for sarcopenic elderly and COPD patients. These recommendations are designed to promote net muscle accretion. Our results indicate that mice on a 70 E% caloric-restriction diet show habitual changes that come close to these recommendations and therefore indicate that CR should be considered as a lifestyle and not simply a diet intervention.


In short, these researchers suggest that pre-meal exercise combined with lifelong CR may be especially beneficial for muscle preservation as the body ages.





[1] J Cachexia Sarcopenia Muscle. 2015 Sep;6(3):253-68. doi: 10.1002/jcsm.12024. Epub

2015 Apr 27.

Behavioural changes are a major contributing factor in the reduction of
sarcopenia in caloric-restricted ageing mice.

van Norren K(1), Rusli F(2), van Dijk M(3), Lute C(2), Nagel J(3), Dijk FJ(3),
Dwarkasing J(4), Boekschoten MV(2), Luiking Y(3), Witkamp RF(4), Müller M(2),
Steegenga WT(2).

BACKGROUND: In rodent models, caloric restriction (CR) with maintenance of
adequate micronutrient supply has been reported to increase lifespan and to
reduce age-induced muscle loss (sarcopenia) during ageing. In the present study,
we further investigated effects of CR on the onset and severity of sarcopenia in
ageing male C57BL/6 J mice. The aim of this study was to investigate whether CR
induces changes in behaviour of the animals that could contribute to the
pronounced health-promoting effects of CR in rodents. In addition, we aimed to
investigate in more detail the effects of CR on the onset and severity of
METHODS: The mice received either an ad libitum diet (control) or a diet matching
70 E% of the control diet ©. Daily activity, body composition (dual energy
X-ray absorptiometry), grip strength, insulin sensitivity, and general agility
and balance were determined at different ages. Mice were killed at 4, 12, 24, and
28 months. Skeletal muscles of the hind limb were dissected, and the muscle
extensor digitorum longus muscle was used for force-frequency measurements. The
musculus tibialis was used for real-time quantitative PCR analysis.
RESULTS: From the age of 12 months, CR animals were nearly half the weight of the
control animals, which was mainly related to a lower fat mass. In the control
group, the hind limb muscles showed a decline in mass at 24 or 28 months of age,
which was not present in the CR group. Moreover, insulin sensitivity (oral
glucose tolerance test) was higher in this group and the in vivo and ex vivo grip
strength did not differ between the two groups. In the hours before food was
provided, CR animals were far more active than control animals, while total daily
activity was not increased. Moreover, agility test indicated that CR animals were
better climbers and showed more climbing behaviours.
CONCLUSIONS: Our study confirms earlier findings that in CR animals less
sarcopenia is present. The mice on the CR diet, however, showed specific
behavioural changes characterized by higher bursts of activity within a short
time frame before consumption of a 70 E% daily meal. We hypothesize that the
positive effects of CR on muscle maintenance in rodents are not merely a direct
consequence of a lower energy intake but also related to a more active behaviour
in a specific time frame. The burst of activity just before immediate start of
eating, might lead to a highly effective use of the restricted protein sources

PMCID: PMC4575557
PMID: 26401472



[2] J Gerontol A Biol Sci Med Sci. 2008 Jun;63(6):556-9.

Attenuation of sarcopenia by dietary restriction in rhesus monkeys.

Colman RJ(1), Beasley TM, Allison DB, Weindruch R.

Author information:
(1)Wisconsin National Primate Research Center, University of Wisconsin-Madison,
1220 Capitol Ct., Madison, WI 53715, USA. rcolman@primate.wisc.edu

Sarcopenia, the loss of muscle mass with normal aging, devastates quality of
life-and related healthcare expenditures are enormous. The prevention or
attenuation of sarcopenia would be an important medical advance. Dietary
restriction (DR) is the only dietary intervention that consistently extends
median and maximum life span, as well as health span in rodents. Evidence
suggests that DR will have a similar effect in primates. Furthermore, DR opposes
sarcopenia in rodents. We tested the hypothesis that DR will reduce age-related
sarcopenia in a nonhuman primate. Thirty adult male rhesus monkeys, half fed a
normal calorie intake and half reduced by 30% in caloric intake, were examined
over 17 years for changes in dual-energy X-ray absorptiometry-estimated skeletal
muscle mass. Body weight-adjusted skeletal muscle mass declined somewhat in both
groups but was far more rapid in the control group. We have shown that moderate,
adult-onset DR can attenuate sarcopenia in a nonhuman primate model.

PMCID: PMC2812805
PMID: 18559628


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