On 2014 Nov 21, Irina M Conboy commented:

Thank you for the positive and constructive comment on our manuscript. We agree in general terms that it would be premature to start prescribing oxtocin to people who suffer from muscle wasting and many of your points suggested to be addressed before the clinical trials are actually being performed or are planned as near future work in our laboratory.

1) How does the short half-life of OT (3-5 minutes) impact the utility of it being a therapeutic agent for sarcopenia? Short half-life does not signify a lack of activity particularly for hormones with physiological short life; and in animal studies once a day single injection of oxytocin sufficed for the enhanced regeneration of old muscle after less than 2 weeks of administration.

2) Could systemic administration of OT suppress appetite and actually exacerbate muscle wasting in the elderly? There is a known problem with obesity in general and in the elderly; obesity exacerbates the lack of mobility (leading to decline in muscle health) and obesity also leads to and aggravates metabolic disorders, which in turn promote muscle wasting. Therefore, suppression of appetite by oxytocin might be actually therapeutic for obese individuals. For those who are frail or have poor appetite due to old age or disease, there should be of course, a caution in recommending oxytocin.

3) What would their dose be when expressed as a human equivalent dose, and how does this relate to what we already know about the maximum safe dose for OT? The therapeutic safe for humans doses of oxytocin will be determined experimentally and this is in our plans. The path to this is well developed and many commercial as well as UC Berkeley services are available. The current clinical use of oxytocin facilitates the development of its use for additional therapeutic applications.

Lastly, similar to many other basic science studies, the authors suggest that OT could impact ‘muscle strength and agility’, but have done no functional or behavioral measurements. As we, and others, have pointed out, the age-related loss of muscle strength is only partially explained by the reduction in muscle mass, as many other neural and muscular factors are involved in age-related muscle weakness (as well as motor function outcomes, such as agility). In fact, a number of papers indicate that an increase in muscle mass does not increase strength in both rodents and humans. Our ongoing work is promising in suggesting that animal strength and agility indeed rely (at least in part) on oxytocin and healthy muscle that regenerates well is obviously innervated/re-innervated better. With respect to experimentally induced increase in muscle mass, e.g. by decrease in tissue remodeling, such unbalanced non-physiological interventions would be predicted not to have sustainable functional improvement in tissue health. In contrast, restoring physiological levels of a hormone that is important for muscle tissue maintenance and declines with age is predicted to lead to successful restoration of both regeneration and function of skeletal muscle. This will be examined in the necessary pre-clinical work, which is in our plans. Of important note, in all single gene KO studies, the age and gender matched littermates provide the necessary controls; as such, premature sacropenia in oxytocin KO mice as compared to the wt littermates (established in our work) signifies that oxytocin is needed not only for muscle regeneration, but also for the maintenance of muscle mass and fiber size.

On 2014 Nov 07, Brian Clark commented:

Oxytocin as a treatment for sarcopenia?

ARISING FROM C. Elabd, W. Cousin, P. Upadhyayula, R.Y. Chen, M.S. Chooljian, J. Li, S. Kung, K.P. Jiang, and I.M. Conboy Nature Communications 5:4082 (2014)

In a very elegant series of experiments Elabd et al. have introduced the intriguing possibility that oxytocin, known for its effects on the reproductive system and more recently on social behaviors, may prove to be useful in treating age-related muscle wasting (i.e., sarcopenia) through an effect on satellite cells [1]. They conclude that “oxytocin (OT) and oxytocin receptor (OTR) agonists might be potentially used as systemically applicable and sustainable molecules for combating the deterioration of muscle mass, strength and agility in the elderly”. Since OT is already approved for use by the FDA, it may be tempting for clinicians to use this conclusion to justify the use of OT in elderly patients suffering from sarcopenia. Caution, however, is needed.

Elabd et al. show convincingly that OT administration in old mice promotes recovery from cardiotoxin-induced muscle injury through an effect on satellite cells. However, they fail to present evidence indicating that OT (or OTR agonist) administration increases muscle mass or muscle function in their older male mice or the OT-KO mice. That is, they did not perform the basic efficacy experiment for such a conclusion to provide proof-of-concept evidence to rationalize translation of this work directly to human application or trials. Additionally, there are a number of issues that must be addressed to support this translation to humans. For example, 1) How does the short half-life of OT (3-5 minutes) impact the utility of it being a therapeutic agent for sarcopenia?; 2) Could systemic administration of OT suppress appetite [2, 3] and actually exacerbate muscle wasting in the elderly?; and 3) What would their dose be when expressed as a human equivalent dose [4], and how does this relate to what we already know about the maximum safe dose for OT? Lastly, similar to many other basic science studies, the authors suggest that OT could impact ‘muscle strength and agility’, but have done no functional or behavioral measurements. As we, and others, have pointed out, the age-related loss of muscle strength is only partially explained by the reduction in muscle mass, as many other neural and muscular factors are involved in age-related muscle weakness (as well as motor function outcomes, such as agility) [5, 6]. In fact, a number of papers indicate that an increase in muscle mass does not increase strength in both rodents [7] and humans [8].

The results of the Elabd et al. study are important because they may open a new area of research, but it is also important that our concerns are recognized in order to prevent OT, which is already approved by the FDA, from being hastily prescribed off-label in an attempt to combat muscle wasting, weakness and/or mobility disability in the elderly.

Brian C. Clark1,2,3, David W. Russ1,4, John N. Howell1,2Anne B. Loucks1,5, Timothy D. Law1,6, Leatha A. Clark1, Kentaro Oki1, Shinichi Amano1, Niladri K. Mahato1, S. Lee Hong1,2,3, Todd M. Manini7

1Ohio Musculoskeletal and Neurological Institute (OMNI), 2Department of Biomedical Sciences, 3Department of Geriatric Medicine, 4School of Rehabilitation and Communication Sciences, 5Department of Biological Sciences, 6Department of Family Medicine at Ohio University, Athens, OH, USA; 7Insnstitute on Aging and Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA

Correspondence: Brian C. Clark, Ph.D. Ohio University Ohio Musculoskeletal and Neurological Institute (OMNI), 250 Irvine Hall Athens, OH 45701 740-593-2354 (O) 740-597-2778 clarkb2@ohio.edu

REFERENCES

1. 1. Elabd, C., et al., Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nat Commun, 2014. 5: p. 4082.
2. 2. Sabatier, N., G. Leng, and J. Menzies, Oxytocin, feeding, and satiety. Front Endocrinol (Lausanne), 2013. 4: p. 35.
3. 3. Morton, G.J., et al., Peripheral oxytocin suppresses food intake and causes weight loss in diet-induced obese rats. Am J Physiol Endocrinol Metab, 2012. 302(1): p. E134-44.
4. 4. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, U.S.D.o.H.a.H. Services., Editor 2005, Food and Drug Adminstration. Center for Drug Evaluation and Research.: Rockville, MD. p. 1-30.
5. 5. Clark, B.C. and T.M. Manini, Sarcopenia =/= dynapenia. J Gerontol A Biol Sci Med Sci, 2008. 63(8): p. 829-34.
6. 6. Russ, D.W., et al., Evolving concepts on the age-related changes in "muscle quality". Journal of cachexia, sarcopenia and muscle, 2012.
7. 7. Personius, K.E., et al., Grip force, EDL contractile properties, and voluntary wheel running after postdevelopmental myostatin depletion in mice. J Appl Physiol (1985), 2010. 109(3): p. 886-94.
8. 8. Delmonico, M.J., et al., Longitudinal study of muscle strength, quality, and adipose tissue infiltration. Am J Clin Nutr, 2009. 90(6): p. 1579-85.

On 2014 Nov 07, Brian Clark commented:

Oxytocin as a treatment for sarcopenia?

ARISING FROM C. Elabd, W. Cousin, P. Upadhyayula, R.Y. Chen, M.S. Chooljian, J. Li, S. Kung, K.P. Jiang, and I.M. Conboy Nature Communications 5:4082 (2014)

In a very elegant series of experiments Elabd et al. have introduced the intriguing possibility that oxytocin, known for its effects on the reproductive system and more recently on social behaviors, may prove to be useful in treating age-related muscle wasting (i.e., sarcopenia) through an effect on satellite cells [1]. They conclude that “oxytocin (OT) and oxytocin receptor (OTR) agonists might be potentially used as systemically applicable and sustainable molecules for combating the deterioration of muscle mass, strength and agility in the elderly”. Since OT is already approved for use by the FDA, it may be tempting for clinicians to use this conclusion to justify the use of OT in elderly patients suffering from sarcopenia. Caution, however, is needed.

Elabd et al. show convincingly that OT administration in old mice promotes recovery from cardiotoxin-induced muscle injury through an effect on satellite cells. However, they fail to present evidence indicating that OT (or OTR agonist) administration increases muscle mass or muscle function in their older male mice or the OT-KO mice. That is, they did not perform the basic efficacy experiment for such a conclusion to provide proof-of-concept evidence to rationalize translation of this work directly to human application or trials. Additionally, there are a number of issues that must be addressed to support this translation to humans. For example, 1) How does the short half-life of OT (3-5 minutes) impact the utility of it being a therapeutic agent for sarcopenia?; 2) Could systemic administration of OT suppress appetite [2, 3] and actually exacerbate muscle wasting in the elderly?; and 3) What would their dose be when expressed as a human equivalent dose [4], and how does this relate to what we already know about the maximum safe dose for OT? Lastly, similar to many other basic science studies, the authors suggest that OT could impact ‘muscle strength and agility’, but have done no functional or behavioral measurements. As we, and others, have pointed out, the age-related loss of muscle strength is only partially explained by the reduction in muscle mass, as many other neural and muscular factors are involved in age-related muscle weakness (as well as motor function outcomes, such as agility) [5, 6]. In fact, a number of papers indicate that an increase in muscle mass does not increase strength in both rodents [7] and humans [8].

The results of the Elabd et al. study are important because they may open a new area of research, but it is also important that our concerns are recognized in order to prevent OT, which is already approved by the FDA, from being hastily prescribed off-label in an attempt to combat muscle wasting, weakness and/or mobility disability in the elderly.

Brian C. Clark1,2,3, David W. Russ1,4, John N. Howell1,2Anne B. Loucks1,5, Timothy D. Law1,6, Leatha A. Clark1, Kentaro Oki1, Shinichi Amano1, Niladri K. Mahato1, S. Lee Hong1,2,3, Todd M. Manini7

1Ohio Musculoskeletal and Neurological Institute (OMNI), 2Department of Biomedical Sciences, 3Department of Geriatric Medicine, 4School of Rehabilitation and Communication Sciences, 5Department of Biological Sciences, 6Department of Family Medicine at Ohio University, Athens, OH, USA; 7Insnstitute on Aging and Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA

Correspondence: Brian C. Clark, Ph.D. Ohio University Ohio Musculoskeletal and Neurological Institute (OMNI), 250 Irvine Hall Athens, OH 45701 740-593-2354 (O) 740-597-2778 clarkb2@ohio.edu

REFERENCES

1. 1. Elabd, C., et al., Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nat Commun, 2014. 5: p. 4082.
2. 2. Sabatier, N., G. Leng, and J. Menzies, Oxytocin, feeding, and satiety. Front Endocrinol (Lausanne), 2013. 4: p. 35.
3. 3. Morton, G.J., et al., Peripheral oxytocin suppresses food intake and causes weight loss in diet-induced obese rats. Am J Physiol Endocrinol Metab, 2012. 302(1): p. E134-44.
4. 4. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, U.S.D.o.H.a.H. Services., Editor 2005, Food and Drug Adminstration. Center for Drug Evaluation and Research.: Rockville, MD. p. 1-30.
5. 5. Clark, B.C. and T.M. Manini, Sarcopenia =/= dynapenia. J Gerontol A Biol Sci Med Sci, 2008. 63(8): p. 829-34.
6. 6. Russ, D.W., et al., Evolving concepts on the age-related changes in "muscle quality". Journal of cachexia, sarcopenia and muscle, 2012.
7. 7. Personius, K.E., et al., Grip force, EDL contractile properties, and voluntary wheel running after postdevelopmental myostatin depletion in mice. J Appl Physiol (1985), 2010. 109(3): p. 886-94.
8. 8. Delmonico, M.J., et al., Longitudinal study of muscle strength, quality, and adipose tissue infiltration. Am J Clin Nutr, 2009. 90(6): p. 1579-85.

On 2014 Nov 21, Irina M Conboy commented:

Thank you for the positive and constructive comment on our manuscript. We agree in general terms that it would be premature to start prescribing oxtocin to people who suffer from muscle wasting and many of your points suggested to be addressed before the clinical trials are actually being performed or are planned as near future work in our laboratory.

1) How does the short half-life of OT (3-5 minutes) impact the utility of it being a therapeutic agent for sarcopenia? Short half-life does not signify a lack of activity particularly for hormones with physiological short life; and in animal studies once a day single injection of oxytocin sufficed for the enhanced regeneration of old muscle after less than 2 weeks of administration.

2) Could systemic administration of OT suppress appetite and actually exacerbate muscle wasting in the elderly? There is a known problem with obesity in general and in the elderly; obesity exacerbates the lack of mobility (leading to decline in muscle health) and obesity also leads to and aggravates metabolic disorders, which in turn promote muscle wasting. Therefore, suppression of appetite by oxytocin might be actually therapeutic for obese individuals. For those who are frail or have poor appetite due to old age or disease, there should be of course, a caution in recommending oxytocin.

3) What would their dose be when expressed as a human equivalent dose, and how does this relate to what we already know about the maximum safe dose for OT? The therapeutic safe for humans doses of oxytocin will be determined experimentally and this is in our plans. The path to this is well developed and many commercial as well as UC Berkeley services are available. The current clinical use of oxytocin facilitates the development of its use for additional therapeutic applications.

Lastly, similar to many other basic science studies, the authors suggest that OT could impact ‘muscle strength and agility’, but have done no functional or behavioral measurements. As we, and others, have pointed out, the age-related loss of muscle strength is only partially explained by the reduction in muscle mass, as many other neural and muscular factors are involved in age-related muscle weakness (as well as motor function outcomes, such as agility). In fact, a number of papers indicate that an increase in muscle mass does not increase strength in both rodents and humans. Our ongoing work is promising in suggesting that animal strength and agility indeed rely (at least in part) on oxytocin and healthy muscle that regenerates well is obviously innervated/re-innervated better. With respect to experimentally induced increase in muscle mass, e.g. by decrease in tissue remodeling, such unbalanced non-physiological interventions would be predicted not to have sustainable functional improvement in tissue health. In contrast, restoring physiological levels of a hormone that is important for muscle tissue maintenance and declines with age is predicted to lead to successful restoration of both regeneration and function of skeletal muscle. This will be examined in the necessary pre-clinical work, which is in our plans. Of important note, in all single gene KO studies, the age and gender matched littermates provide the necessary controls; as such, premature sacropenia in oxytocin KO mice as compared to the wt littermates (established in our work) signifies that oxytocin is needed not only for muscle regeneration, but also for the maintenance of muscle mass and fiber size.