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New Insights into Muscle Loss

Dean Pomerleau

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[Note: This is another post that would fit best on a "Non-CR health science" forum. I'm posting it here on "CR Practice" because it has to do with a concern of people practicing CR.]


Excessive muscle loss and wasting (sarcopenia) is a concern as people age, and since CRers weigh less, they also (generally) have less muscle mass to lose as they age, so it is a potential issue for us too.


This new study [1], described in this popular press article, provides new understanding of this problem. It describes research identifying a protein (ATF4) that appears to be causally related to muscle wasting. Here is the main points of the research, summarized in the article:


The protein, ATF4, is a transcription factor that alters gene expression in skeletal muscle, causing reduction of muscle protein synthesis, strength, and mass. The UI study also identifies two natural compounds, one found in apples and one found in green tomatoes, which reduce ATF4 activity in aged skeletal muscle. The findings, which were published online Sept. 3 in the Journal of Biological Chemistry, could lead to new therapies for age-related muscle weakness and atrophy.


Previously, Adams and his team had identified ursolic acid, which is found in apple peel, and tomatidine, which comes from green tomatoes, as small molecules that can prevent acute muscle wasting caused by starvation and inactivity.


An example of the previous work by these authors that identified ursolic acid and tomatidine as protective against muscle wasting is this publication [2]. The possible downside of these compounds is that they appear to have their effect by "enhancing skeletal muscle insulin/IGF-I signaling", which CR is known to downregulate, an effect which may very well be important for CR's health/longevity benefits. 


In the meantime, I'm going to continue exercising, eating apple peels and tomatoes (although usually red rather than green), to hopefully maintain skeletal muscle mass and health.





[1] J Biol Chem. 2015 Sep 3. pii: jbc.M115.681445. [Epub ahead of print]

Identification and Small Molecule Inhibition of an ATF4-dependent Pathway to
Age-related Skeletal Muscle Weakness and Atrophy.

Ebert SM(1), Dyle MC(1), Bullard SA(1), Dierdorff JM(1), Murry DJ(1), Fox DK(1),
Bongers KS(1), Lira VA(1), Meyerholz DK(1), Talley JJ(2), Adams CM(3).

Aging reduces skeletal muscle mass and strength, but the underlying molecular
mechanisms remain elusive. Here, we used mouse models to investigate molecular
mechanisms of age-related skeletal muscle weakness and atrophy, as well as new
potential interventions for these conditions. We identified two small molecules
that significantly reduce age-related deficits in skeletal muscle strength,
quality and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and
tomatidine (a steroidal alkaloid derived from green tomatoes). Because small
molecule inhibitors can sometimes provide mechanistic insight into disease
processes, we used ursolic acid and tomatidine to investigate the pathogenesis of
age-related muscle weakness and atrophy. We found that ursolic acid and
tomatidine generate hundreds of small positive and negative changes in mRNA
levels in aged skeletal muscle, and the mRNA expression signatures of the two
compounds are remarkably similar. Interestingly, a subset of the mRNAs are
repressed by ursolic acid and tomatidine in aged muscle are positively regulated
by the transcription factor ATF4. Based on this finding, we investigated ATF4 as
a potential mediator of age-related muscle weakness and atrophy. We found that a
targeted reduction in skeletal muscle ATF4 expression reduces age-related
deficits in skeletal muscle strength, quality and mass, similar to ursolic acid
and tomatidine. These results elucidate ATF4 as a critical mediator of
age-related muscle weakness and atrophy. In addition, these results identify
ursolic acid and tomatidine as potential agents and/or lead compounds for
reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle.

Copyright © 2015, The American Society for Biochemistry and Molecular Biology.

PMID: 26338703




[2] Cell Metab. 2011 Jun 8;13(6):627-38. doi: 10.1016/j.cmet.2011.03.020.

mRNA expression signatures of human skeletal muscle atrophy identify a natural
compound that increases muscle mass.

Kunkel SD(1), Suneja M, Ebert SM, Bongers KS, Fox DK, Malmberg SE, Alipour F,
Shields RK, Adams CM.

Skeletal muscle atrophy is a common and debilitating condition that lacks a
pharmacologic therapy. To develop a potential therapy, we identified 63 mRNAs
that were regulated by fasting in both human and mouse muscle, and 29 mRNAs that
were regulated by both fasting and spinal cord injury in human muscle. We used
these two unbiased mRNA expression signatures of muscle atrophy to query the
Connectivity Map, which singled out ursolic acid as a compound whose signature
was opposite to those of atrophy-inducing stresses. A natural compound enriched
in apples, ursolic acid reduced muscle atrophy and stimulated muscle hypertrophy
in mice. It did so by enhancing skeletal muscle insulin/IGF-I signaling and
inhibiting atrophy-associated skeletal muscle mRNA expression. Importantly,
ursolic acid's effects on muscle were accompanied by reductions in adiposity,
fasting blood glucose, and plasma cholesterol and triglycerides. These findings
identify a potential therapy for muscle atrophy and perhaps other metabolic

PMCID: PMC3120768
PMID: 21641545

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Here is more interesting information about ATF4, the protein that apparently increases muscle wasting, and its relation to CR (perhaps this thread should have posted to CR Science after all!).


This study [1] in mice found that obesity prone Ob/Ob mice had higher levels of the muscle-waste-inducing protein ATF4 than normal mice when both were fed ad lib, but after 4 weeks of calorie restriction, the level of ATF4 in the Ob/Ob mice dropped to near that of the normal mice. Here is the graph (click to enlarge):




So this suggests that CR should protect us from muscle wasting as a result of elevated levels of this protein, although muscle loss associated with general weight loss due to calorie restriction is still a concern for all of us hoping to be robust in our old age.





[1] Biochem Biophys Res Commun. 2011 Jan 7;404(1):339-44. doi:

10.1016/j.bbrc.2010.11.120. Epub 2010 Dec 4.

Caloric restriction decreases ER stress in liver and adipose tissue in ob/ob

Tsutsumi A(1), Motoshima H, Kondo T, Kawasaki S, Matsumura T, Hanatani S, Igata
M, Ishii N, Kinoshita H, Kawashima J, Taketa K, Furukawa N, Tsuruzoe K, Nishikawa
T, Araki E.

Author information:
(1)Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto
University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.

Endoplasmic reticulum (ER) stress plays a crucial role in the development of
insulin resistance and diabetes. Although caloric restriction (CR) improves
obesity-related disorders, the effects of CR on ER stress in obesity remain
unknown. To investigate how CR affects ER stress in obesity, ob/ob mice were
assigned to either ad libitum (AL) (ob-AL) or CR (ob-CR) feeding (2 g food/day)
for 1-4 weeks. The body weight (BW) of ob-CR mice decreased to the level of lean
AL-fed littermates (lean-AL) within 2 weeks. BW of lean-AL and ob-CR mice was
less than that of ob-AL mice. The ob-CR mice showed improved glucose tolerance
and hepatic insulin action compared with ob-AL mice. Levels of ER stress markers
such as phosphorylated PKR-like ER kinase (PERK) and eukaryotic translation
initiation factor 2α and the mRNA expression of activating transcription factor 4
were significantly higher in the liver and epididymal fat from ob-AL mice
compared with lean-AL mice. CR for 2 and 4 weeks significantly reduced all of
these markers to less than 35% and 50%, respectively, of the levels in ob-AL
mice. CR also significantly reduced the phosphorylation of insulin receptor
substrate (IRS)-1 and c-Jun NH(2)-terminal kinase (JNK) in ob/ob mice. The
CR-mediated decrease in PERK phosphorylation was similar to that induced by
4-phenyl butyric acid, which reduces ER stress in vivo. In conclusion, CR reduced
ER stress and improved hepatic insulin action by suppressing JNK-mediated IRS-1
serine-phosphorylation in ob/ob mice.

Copyright © 2010 Elsevier Inc. All rights reserved.

PMID: 21134353

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Hi Dean!


In the days of the CR List, Michael Rae made a post listed as "Off Topic".  The post exacly discussed a possible agent for avoiding -- maybe even partially reversing -- sarcopenia.  Michael posted this "off topic" post in the context of being the Science Writer for SENS.


The post indicated that SENS had partially funded a research study done at UC Berkely.  The study involved parabiosis in mice:  older mice connected by parabiosis to young mice experienced partial reversal of what sarcopenia had occurred; while the younger mice showed some loss of muscle.Further research suggested that the "good" molecule in the blood of young mice (that was depleted inthe old mice) was Oxytocin -- the "feel good" hormone -- a small and simple molecule.


The Berkeley researchers found that, when injecting Oxytocin into old mice, their sarcopenia was partially reversed, almost to youthful levels.


(I'll post more about this a little later.)


  -- Saul

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Hi again, Dean!


I think so too.  I looked up and printed out the original Press Release from UCB.  I then went to my Endocrinologist (who monitors my Osteoporosis), Dr. Steven Wittlin, Chief of the Department of Endocrinology at Strong Memorial Hospital (Hospital recently renamed UR Medicine).  I showed him the print-out, and indicated interest in being in a Research Study.


Dr. Wittlin was well aware of the article-- he had already obtained the original research papers of the authors -- and was very interested in doing a double-blind study, of the effects of Oxytocin supplementation on older humans. He wanted to get the UR Gerontologists involved; unfortunately, they weren't interested.


I'd be delighted to participate in such a study at any good university or research institution, whether or not it required me to travel. 


  -- Saul

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Here is a good podcast from Radio National Australia talking with a nutritionist about muscle loss in people over 70 and the need for more dietary protein and exercise.




It has some good advice about weight. If you need to lose weight, do it in your 40s or 50s. If you lose weight over 60, it is VERY difficult to avoid losing substantial amounts of muscle, which will lead to frailty and be a net detriment to your health. And once gone, it's very difficult to regain the muscle mass when you are older.



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Hi Dean!


I remember Warren Taylor posting on the same topic in the days of the (good old) CR and CRCOMM lists.


I remember my response:


IMO, one's physical age is not the same as one's cronological age.  I believe the (probably correct) recommendation that older people should up their protein, should apply to PHYSICAL AGE, not CRONOLOGICAL AGE.  And I believe that my physical age is younger than my cronological age (of 76).  So, I'm sticking to a low protein, low calorie, high fiber, high complex carb (mostly raw veggies) diet.


I believe my lower physical age [if indeed I am correct] is probably mostly due to the benefits of long-time (approaching 20 years) of Calorie Restriction with adequate nutrition.




  -- Saul

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Hi Saul:


Based on our previous posts here, we seem to have comparable bio/chrono age discrepancies. I would attribute mine to 12 years of insufficiently strict CR (BMI today = 22), and a high (complex) carb diet I started in 1974. fwiw.



Thanks Rodney and Saul. To me, and I think to many others, your experiences with long-term CR, particularly as you reach a relatively advanced age, are worth a great deal indeed.


Saul, you especially are an interesting "case study", having been living as a serious, high-carb, low-fat CRer with well-documented low bone density for many years without bone fracture s, right?


It's insights and anecdotes like these that I think we need more of if we are to document and optimize the practice of human CR. I wish other CR veterans like you two (who we know are lurking on these forums) would share there experiences with CR, both what has worked well and what hasn't. What do you wish you knew 15,20,or 25 years ago related to CR that you know today?


For any veteran who is reluctant for whatever reason to post directly about your experiences, I'd be happy to serve as a conduit, keeping you anonymous if you wish. Just email me at dean@pomerleaus.com.



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  • 5 months later...

Getting back to Dean's discussion of urosolic acid, and his suggesting it is counter-CR due to IGF-1 being increased, the below paper seems to suggest that it is a CR mimetic.  But I wonder how many apple (peels) one would need to eat to get as much of it as what was used.  This may pertain to the recent "apples vs mortality" thread also.


"[urosolic acid] indirectly mimicked beneficial effects of short-term calorie restriction and exercise (fast-oxidative) by directing the skeletal muscle composition toward oxidative metabolism.


Short-term ursolic acid promotes skeletal muscle rejuvenation through enhancing of SIRT1 expression and satellite cells proliferation.
Bakhtiari N, Hosseinkhani S, Soleimani M, Hemmati R, Noori-Zadeh A, Javan M, Tashakor A.
Biomed Pharmacother. 2016 Mar;78:185-96. doi: 10.1016/j.biopha.2016.01.010. Epub 2016 Feb 1.
PMID: 26898441
Ursolic acid (UA) is a triterpenoid compound, which exerts its influences on the skeletal muscles. However, the mechanisms underlying these effects are still unclear. In this study, muscle satellite cells were isolated and purified by high-throughput pre-plating method (∼>60%) from 10 days old mice skeletal muscles. Evaluation of paired-box 7 (Pax7) expressions then confirmed the purification. Treatment of the cells with UA showed that UA up-regulated SIRT1 (∼35 folds) and overexpressed PGC-1α (∼175 folds) gene significantly. Moreover, the number of muscle satellite cells, which accompanied by initiation of neomyogenesis in the animal skeletal muscles, was increased (∼3.4 times). We also evaluated UA-mediated changes in the cellular energy status in the skeletal muscles. The results revealed that in the UA-treated mice, ATP and ADP contents in the various skeletal muscle tissue types, including: Gastrocnemius (Gas), Tibialis Anterior (Tib) and Gluteus Maximus (Glu) have been significantly decreased (P≤0.001); 2.2, 3.2, 2 times for ATP, and 9.6, 35.7, 11.6 times for ADP, respectively; however to compensate this process mitochondrial biogenesis occurred (12.33%±1.5 times). Furthermore, a rise in ATP/ADP ratio was observed 2.5, 4.5, 2.05 times for Gas, Tib and Glu muscles, respectively (P≤0.001). Alternatively, UA enhanced the expression of myoglobin (∼2 folds) in concert with remodeling of glycolytic muscle fibers to mainly fast IIA (∼30%) and slow-twitch (∼4%) types as well. Finally, our study indicated that UA indirectly mimicked beneficial effects of short-term calorie restriction and exercise (fast-oxidative) by directing the skeletal muscle composition toward oxidative metabolism.
Muscle satellite cells; PGC-1α; SIRT1; Ursolic acid
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