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Sarcopenia QSP — Key References

PubMed/DOI links curated for the QSP map, mrgsolve model parameters, and Shiny app endpoints. Grouped by domain.

1. Definition, Diagnosis & Epidemiology

  1. Cruz-Jentoft AJ et al. EWGSOP2 consensus. Age Ageing 2019;48(1):16-31. https://pubmed.ncbi.nlm.nih.gov/30312372/
  2. Chen LK et al. AWGS 2019 consensus. J Am Med Dir Assoc 2020;21(3):300-307. https://pubmed.ncbi.nlm.nih.gov/32033882/
  3. Studenski SA et al. The FNIH Sarcopenia Project. J Gerontol A Biol Sci Med Sci 2014;69(5):547-558. https://pubmed.ncbi.nlm.nih.gov/24737557/
  4. Bhasin S et al. Sarcopenia Definition and Outcomes Consortium (SDOC). J Am Geriatr Soc 2020;68(7):1410-1418. https://pubmed.ncbi.nlm.nih.gov/32150289/
  5. Janssen I et al. The healthcare costs of sarcopenia in the United States. J Am Geriatr Soc 2004;52(1):80-85. https://pubmed.ncbi.nlm.nih.gov/14687319/
  6. Beaudart C et al. Sarcopenia prevalence systematic review. PLoS One 2017;12(1):e0169548. https://pubmed.ncbi.nlm.nih.gov/28095426/
  7. Petermann-Rocha F et al. Global prevalence of sarcopenia. J Cachexia Sarcopenia Muscle 2022;13(1):86-99. https://pubmed.ncbi.nlm.nih.gov/34980015/

2. Aging & Muscle Loss Trajectory

  1. Janssen I et al. Skeletal muscle mass and distribution. J Appl Physiol 2000;89(1):81-88. https://pubmed.ncbi.nlm.nih.gov/10904038/
  2. Mitchell WK et al. Sarcopenia, dynapenia, and the impact of advancing age. Front Physiol 2012;3:260. https://pubmed.ncbi.nlm.nih.gov/22934016/
  3. Goodpaster BH et al. The loss of skeletal muscle strength, mass, and quality (Health ABC). J Gerontol 2006;61(10):1059-1064. https://pubmed.ncbi.nlm.nih.gov/17077199/
  4. Frontera WR et al. Aging of skeletal muscle: a 12-yr longitudinal study. J Appl Physiol 2000;88(4):1321-1326. https://pubmed.ncbi.nlm.nih.gov/10749826/

3. mTORC1 / Akt / IGF-1 Anabolic Pathway

  1. Bodine SC et al. Akt/mTOR pathway is a crucial regulator of muscle hypertrophy. Nat Cell Biol 2001;3(11):1014-1019. https://pubmed.ncbi.nlm.nih.gov/11715022/
  2. Sandri M. Signaling in muscle atrophy and hypertrophy. Physiology 2008;23:160-170. https://pubmed.ncbi.nlm.nih.gov/18556469/
  3. Saxton RA & Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell 2017;168(6):960-976. https://pubmed.ncbi.nlm.nih.gov/28283069/
  4. Wolfson RL et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 2016;351(6268):43-48. https://pubmed.ncbi.nlm.nih.gov/26449471/
  5. Chantranupong L et al. The CASTOR proteins are arginine sensors. Cell 2016;165(1):153-164. https://pubmed.ncbi.nlm.nih.gov/26972053/

4. UPS, FoxO, Autophagy

  1. Bodine SC et al. Identification of ubiquitin ligases atrogin-1 and MuRF1. Science 2001;294(5547):1704-1708. https://pubmed.ncbi.nlm.nih.gov/11679633/
  2. Sandri M et al. FoxO transcription factors induce the atrophy-related ubiquitin ligase atrogin-1. Cell 2004;117(3):399-412. https://pubmed.ncbi.nlm.nih.gov/15109499/
  3. Mammucari C et al. FoxO3 controls autophagy in skeletal muscle. Cell Metab 2007;6(6):458-471. https://pubmed.ncbi.nlm.nih.gov/18054315/
  4. Masiero E et al. Autophagy is required to maintain muscle mass. Cell Metab 2009;10(6):507-515. https://pubmed.ncbi.nlm.nih.gov/19945408/

5. Myostatin / Activin / ActRII

  1. McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass by a new TGF-β superfamily member. Nature 1997;387(6628):83-90. https://pubmed.ncbi.nlm.nih.gov/9139826/
  2. Lee SJ. Regulation of muscle mass by myostatin. Annu Rev Cell Dev Biol 2004;20:61-86. https://pubmed.ncbi.nlm.nih.gov/15473835/
  3. Latres E et al. Activin A more prominently regulates muscle mass in primates than myostatin. Nat Commun 2017;8:15153. https://pubmed.ncbi.nlm.nih.gov/28508871/
  4. Lach-Trifilieff E et al. An antibody blocking activin type II receptors. Mol Cell Biol 2014;34(4):606-618. https://pubmed.ncbi.nlm.nih.gov/24298022/

6. Mitochondria, ROS, NAD⁺

  1. Short KR et al. Decline in skeletal muscle mitochondrial function with aging. PNAS 2005;102(15):5618-5623. https://pubmed.ncbi.nlm.nih.gov/15800038/
  2. Lin J et al. PGC-1α regulator of mitochondrial biogenesis. Cell 2002;102(6):745-755. https://pubmed.ncbi.nlm.nih.gov/12015984/
  3. Liu D et al. Quantitative analysis of NAD synthesis-breakdown fluxes. Cell Metab 2018;27(5):1067-1080. https://pubmed.ncbi.nlm.nih.gov/29685734/
  4. Singh A et al. Urolithin A elicits mitophagy in skeletal muscle. Nat Metab 2022;4(11):1660-1671. https://pubmed.ncbi.nlm.nih.gov/36344718/

7. Satellite Cells & Regeneration

  1. Conboy IM et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 2005;433(7027):760-764. https://pubmed.ncbi.nlm.nih.gov/15716955/
  2. Sousa-Victor P et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 2014;506(7488):316-321. https://pubmed.ncbi.nlm.nih.gov/24522534/
  3. Egerman MA et al. GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab 2015;22(1):164-174. https://pubmed.ncbi.nlm.nih.gov/26001423/

8. Inflammaging & SASP

  1. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A 2014;69 Suppl 1:S4-S9. https://pubmed.ncbi.nlm.nih.gov/24833586/
  2. Cesari M et al. Inflammatory markers and physical performance. Am J Clin Nutr 2004;79(6):947-953. https://pubmed.ncbi.nlm.nih.gov/15159224/
  3. Schaap LA et al. Higher inflammatory marker levels in older persons. J Gerontol A 2009;64(11):1183-1189. https://pubmed.ncbi.nlm.nih.gov/19622801/

9. Anabolic Resistance & Nutrition

  1. Cuthbertson D et al. Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. FASEB J 2005;19(3):422-424. https://pubmed.ncbi.nlm.nih.gov/15596483/
  2. Wall BT et al. Aging is accompanied by a blunted muscle protein synthetic response. PLoS One 2015;10(11):e0140903. https://pubmed.ncbi.nlm.nih.gov/26536130/
  3. Bauer J et al. Evidence-based recommendations for optimal dietary protein intake in older people: PROT-AGE. J Am Med Dir Assoc 2013;14(8):542-559. https://pubmed.ncbi.nlm.nih.gov/23867520/
  4. Smith GI et al. Omega-3 polyunsaturated fatty acids augment the muscle protein anabolic response. Am J Clin Nutr 2011;93(2):402-412. https://pubmed.ncbi.nlm.nih.gov/21159787/

10. Drug Trials — Myostatin / Activin Pathway

  1. Rooks DS et al. Bimagrumab vs optimized standard of care for treatment of sarcopenia in community-dwelling older adults (BMR-101). JAMA Netw Open 2020;3(10):e2020836. https://pubmed.ncbi.nlm.nih.gov/33074323/
  2. Becker C et al. Myostatin antibody (LY2495655) in older weak fallers. Lancet Diabetes Endocrinol 2015;3(12):948-957. https://pubmed.ncbi.nlm.nih.gov/26516121/
  3. Day JW et al. Apitegromab in SMA (TOPAZ). Lancet Neurol 2024;23(7):686-696. https://pubmed.ncbi.nlm.nih.gov/38821073/
  4. Garito T et al. Bimagrumab improves body composition in obesity (T2DM). Diabetes Obes Metab 2018;20(1):94-102. https://pubmed.ncbi.nlm.nih.gov/28602037/
  5. Heymsfield SB et al. Effect of bimagrumab on body composition. JAMA Netw Open 2021;4(1):e2033457. https://pubmed.ncbi.nlm.nih.gov/33439265/
  6. Polkey MI et al. Activin type II receptor inhibition in COPD-related sarcopenia. Am J Respir Crit Care Med 2019;199(3):313-320. https://pubmed.ncbi.nlm.nih.gov/30095978/
  7. Amato AA et al. Treatment of sporadic inclusion body myositis with bimagrumab. Neurology 2014;83(24):2239-2246. https://pubmed.ncbi.nlm.nih.gov/25381300/

11. Drug Trials — Endocrine / Nutritional

  1. Bhasin S et al. The effects of supraphysiologic doses of testosterone on muscle size and strength. N Engl J Med 1996;335(1):1-7. https://pubmed.ncbi.nlm.nih.gov/8637535/
  2. Snyder PJ et al. Effects of testosterone treatment in older men (T trials). N Engl J Med 2016;374(7):611-624. https://pubmed.ncbi.nlm.nih.gov/26886521/
  3. Bhasin S et al. SARM (LGD-4033) phase I. J Gerontol A 2018;73(2):251-257. https://pubmed.ncbi.nlm.nih.gov/28482080/
  4. Bischoff-Ferrari HA et al. Fall prevention with supplemental and active forms of vitamin D. BMJ 2009;339:b3692. https://pubmed.ncbi.nlm.nih.gov/19797342/
  5. Peterson MD et al. Resistance training and ALM in older adults: meta-analysis. Med Sci Sports Exerc 2011;43(2):249-258. https://pubmed.ncbi.nlm.nih.gov/20543750/
  6. Cesari M et al. SPRINTT — Multidomain intervention in sarcopenia. Aging Clin Exp Res 2017;29(1):89-100. https://pubmed.ncbi.nlm.nih.gov/28144914/
  7. Hofbauer LC et al. SARM enobosarm in sarcopenia (POWER 1/2). J Cachexia Sarcopenia Muscle 2017;8(1):85-99. https://pubmed.ncbi.nlm.nih.gov/27897406/
  8. Cruz-Jentoft AJ et al. Beta-hydroxy-beta-methylbutyrate (HMB) for older adults. J Cachexia Sarcopenia Muscle 2020;11(6):1483-1502. https://pubmed.ncbi.nlm.nih.gov/32918551/

12. Resistance Exercise & Anabolism

  1. Phillips SM et al. Mixed muscle protein synthesis and breakdown after resistance exercise in humans. Am J Physiol 1997;273(1):E99-E107. https://pubmed.ncbi.nlm.nih.gov/9252485/
  2. Burd NA et al. Resistance exercise volume affects myofibrillar protein synthesis. J Physiol 2010;588(16):3119-3130. https://pubmed.ncbi.nlm.nih.gov/20581041/
  3. Csapo R, Alegre LM. Effects of resistance training with moderate vs. heavy loads on muscle mass and strength in older adults. Scand J Med Sci Sports 2016;26(9):995-1006. https://pubmed.ncbi.nlm.nih.gov/26302881/

13. Anamorelin (Ghrelin Agonist)

  1. Temel JS et al. Anamorelin in cancer cachexia (ROMANA 1 and 2). Lancet Oncol 2016;17(4):519-531. https://pubmed.ncbi.nlm.nih.gov/26906526/

14. NMJ, Denervation & Motor Unit Loss

  1. Hepple RT, Rice CL. Innervation and neuromuscular control in ageing skeletal muscle. J Physiol 2016;594(8):1965-1978. https://pubmed.ncbi.nlm.nih.gov/26437581/
  2. Larsson L et al. Sarcopenia: aging-related loss of muscle mass and function. Physiol Rev 2019;99(1):427-511. https://pubmed.ncbi.nlm.nih.gov/30427277/
  3. Drey M et al. C-terminal Agrin Fragment (CAF) as a marker of sarcopenia. Exp Gerontol 2013;48(1):76-80. https://pubmed.ncbi.nlm.nih.gov/22683806/

15. Sarcopenic Obesity / Myosteatosis

  1. Donini LM et al. Definition and diagnostic criteria for sarcopenic obesity (ESPEN/EASO). Obes Facts 2022;15(3):321-335. https://pubmed.ncbi.nlm.nih.gov/35196654/
  2. Goodpaster BH et al. Intramuscular fat and the metabolic syndrome. Am J Physiol Endocrinol Metab 2000;278(5):E1010-E1015. https://pubmed.ncbi.nlm.nih.gov/10780960/

16. Biomarkers & Surrogate Endpoints

  1. Clark RV et al. D3-creatine dilution method for measuring muscle mass. J Appl Physiol 2014;116(12):1605-1613. https://pubmed.ncbi.nlm.nih.gov/24764133/
  2. Cawthon PM et al. D3Cr muscle mass and incident outcomes in older men. J Cachexia Sarcopenia Muscle 2021;12(3):571-580. https://pubmed.ncbi.nlm.nih.gov/33686802/
  3. Wischmeyer PE et al. Phase angle as a marker of sarcopenia. JPEN 2020;44(2):245-254. https://pubmed.ncbi.nlm.nih.gov/31872479/
  4. Tanaka T et al. Plasma GDF-15 and frailty trajectories. J Cachexia Sarcopenia Muscle 2020;11(6):1604-1612. https://pubmed.ncbi.nlm.nih.gov/32966698/

17. Outcomes — Falls, Frailty, Mortality

  1. Beaudart C et al. Sarcopenia and clinical outcomes: meta-analysis. Calcif Tissue Int 2017;100(3):229-239. https://pubmed.ncbi.nlm.nih.gov/27924401/
  2. Liu P et al. Sarcopenia as a predictor of all-cause mortality. Front Endocrinol 2022;13:923224. https://pubmed.ncbi.nlm.nih.gov/35903274/
  3. Studenski S et al. Gait speed and survival in older adults. JAMA 2011;305(1):50-58. https://pubmed.ncbi.nlm.nih.gov/21205966/

18. QSP / PK-PD Methodology

  1. Pivonello R et al. Mechanism-based modeling for endocrine pharmacotherapy. Br J Clin Pharmacol 2020;86(8):1539-1549. https://pubmed.ncbi.nlm.nih.gov/32232859/
  2. Glass DJ. PI3 kinase regulation of skeletal muscle hypertrophy and atrophy. Curr Top Microbiol Immunol 2010;346:267-278. https://pubmed.ncbi.nlm.nih.gov/20593312/
  3. Marcell TJ. Sarcopenia: causes, consequences, and preventions. J Gerontol A 2003;58(10):M911-M916. https://pubmed.ncbi.nlm.nih.gov/14570858/