Chapter 16 — Quiz

IGF-1, Myostatin Inhibitors, and the Muscle-Building Peptides

22 items. Answer before opening the key.


1. Muscle hypertrophy results from:

A. an increase in the number of muscle fibers in adults B. net protein accretion — synthesis exceeding breakdown, integrated over time C. increased circulating IGF-1 acting on satellite cells D. reduced myostatin expression alone


2. The dominant signal driving muscle hypertrophy is:

A. dietary protein intake B. circulating growth hormone C. mechanical loading D. satellite cell number


3. Satellite cells contribute to muscle growth principally by:

A. secreting IGF-1 into the circulation B. proliferating and fusing into existing fibers, supplying additional nuclei C. replacing damaged fibers with new ones D. inhibiting myostatin locally


4. IGF-1 is:

A. produced mainly by the pituitary B. a 70-amino-acid polypeptide produced largely in the liver in response to GH C. a small molecule structurally related to testosterone D. identical to insulin in sequence


5. Approximately what proportion of circulating IGF-1 is bound to IGF binding proteins?

A. about 10% B. about half C. upward of 99% D. none — IGF-1 circulates free


6. Mecasermin is approved for:

A. sarcopenia in adults over 65 B. severe primary IGF-1 deficiency in children C. muscle wasting in muscular dystrophy D. performance enhancement under medical supervision


7. The most prominent labeled safety concern with mecasermin is:

A. hepatotoxicity B. hypoglycemia C. injection site necrosis D. immune suppression


8. IGF-1 LR3 differs from native IGF-1 principally in that it:

A. binds a different receptor B. has reduced binding-protein affinity and extended activity C. can be taken orally D. is a smaller molecule


9. The fact that IGF-1 LR3 is known by a code rather than a generic name tells you:

A. nothing; naming is arbitrary B. that it is a peptide rather than a protein C. something about its regulatory history — it never reached serious clinical development D. that it is a cosmetic ingredient


10. Myostatin (GDF-8) is:

A. a positive regulator of muscle growth B. a negative regulator of muscle growth — a brake C. a growth hormone secretagogue D. an IGF binding protein


11. Myostatin signals through:

A. the IGF-1 receptor B. the activin receptor type IIB and Smad2/3 C. the GH receptor and JAK/STAT D. a G-protein-coupled receptor


12. Belgian Blue and Piedmontese cattle show "double muscling" because they carry:

A. an inserted growth hormone transgene B. naturally occurring loss-of-function mutations in the myostatin gene C. elevated circulating IGF-1 D. a follistatin overexpression mutation


13. The most important limitation of the double-muscled cattle as evidence for a myostatin drug is:

A. cattle physiology is unrelated to human physiology B. the mutations have never been sequenced C. a developmental knockout is not the same experiment as adult pharmacological blockade D. the effect is too small to be relevant


14. In myostatin-null animals, force per unit of muscle cross-sectional area has been reported to be:

A. increased proportionally with mass B. unchanged C. reduced D. impossible to measure


15. Follistatin is best described as:

A. a 15-residue peptide B. an endogenous glycoprotein of roughly 35–40 kDa that inhibits myostatin and related family members C. a synthetic myostatin analog D. a receptor found on muscle fibers


16. The central finding of the myostatin-pathway programs in muscle disease was that:

A. the drugs failed to engage the target B. lean mass increased without corresponding reliable improvement in strength or function C. function improved but lean mass did not D. neither mass nor function changed


17. In this chapter's rating system, "myostatin / follistatin inhibitors for muscle disease" is rated ⚠️ because:

A. no human data exists B. human data exists and is disappointing C. the mechanism is unproven D. the compounds are unapproved


18. A surrogate endpoint is legitimate for regulatory purposes when:

A. it is cheaper and faster than the outcome B. it is biologically plausible C. it has been validated — shown that intervention-induced change in it reliably produces the corresponding change in the outcome D. the sponsor prespecifies it


19. Contemporary consensus definitions of sarcopenia lead with:

A. low muscle mass B. low muscle strength C. low body weight D. low serum IGF-1


20. Chapter 8 reported that on GLP-1 receptor agonists, lean mass falls while measured physical function improves. Together with this chapter, that pair demonstrates:

A. that lean mass measurements are unreliable B. that GLP-1 drugs build muscle indirectly C. that mass is not function — a dissociation that can run in either direction D. that myostatin inhibitors should be combined with GLP-1 drugs


21. The correct statement of the IGF-1 and cancer relationship is:

A. IGF-1 causes cancer B. IGF-1 has no relationship to cancer risk C. higher circulating IGF-1 has been associated with increased risk of several cancers in observational studies; confounding is substantial and no causal claim is established D. the association has been disproven by genetic studies


22. Why is "follistatin-344 for performance in healthy adults" rated ❌ in a stronger sense than a compound with simply no data?

A. because it is illegal B. because the disease trials that did run failed on function, which is evidence against the claim rather than merely absence of evidence for it C. because it is a protein rather than a peptide D. because it is expensive


Answer key **1. B.** Hypertrophy is net protein accretion over time. Adult humans do not meaningfully add fibers (A), and no single hormone drives it (C, D). **2. C.** Mechanical loading. Protein intake and hormonal signaling are permissive and modulatory; load is the initiating stimulus, and its removal produces loss within days. **3. B.** Satellite cells fuse into existing fibers and supply nuclei, addressing the myonuclear domain constraint on fiber growth. **4. B.** A 70-amino-acid polypeptide, made largely in the liver in response to GH, structurally related to proinsulin — not identical to insulin. **5. C.** Upward of 99% is bound, mostly to IGFBP-3 in a ternary complex with the acid-labile subunit. This is why total IGF-1 and biologically available IGF-1 are different numbers. **6. B.** Severe primary IGF-1 deficiency in children (and GH gene deletion with neutralizing antibodies to GH). It is a pediatric growth indication, not a muscle or adult indication. **7. B.** Hypoglycemia, because IGF-1 resembles insulin closely enough to engage insulin receptors at sufficient concentration. **8. B.** An N-terminal extension and a position-3 substitution reduce IGFBP affinity, leaving more free and extending activity. It is not orally available and it acts at the same receptor. **9. C.** Per Chapter 1 §1.8, the international naming authority assigns stem names to compounds in serious clinical development. A persistent laboratory code is a fact about regulatory history. **10. B.** A negative regulator — the brake. Loss of function releases growth. **11. B.** Ligand → ActRIIB → type I receptor → Smad2/3 → nucleus, with parallel damping of Akt/mTOR. **12. B.** Both breeds carry loss-of-function mutations in the myostatin gene; breeders selected for a knockout without knowing it existed. **13. C.** The animals developed without myostatin through the period when fiber number is set, so much of their phenotype is hyperplasia. Adult blockade is a different intervention on a different substrate. **14. C.** Reduced — bigger and, gram for gram, weaker. This finding anticipates the human trial results. **15. B.** A glycosylated endogenous protein, well above peptide size, that binds myostatin, activin A, GDF-11, and some BMPs. **16. B.** Mass rose; function did not reliably follow. The drugs *did* engage the target — that is what makes the result so instructive. **17. B.** ⚠️ here reflects the existence of substantial human data that disappointed, not the absence of data. Note that this makes the claim's position worse, not better, than an unstudied one. **18. C.** Validation is a property of the surrogate–outcome–intervention triple. Plausibility (B) and convenience (A) are not sufficient. **19. B.** Low muscle strength, with low mass as confirmatory and physical performance grading severity. The field demoted mass on its own evidence. **20. C.** Mass is not function. The dissociation ran one way in Chapter 8 and the other way here; the shared lesson is that only measurement settles it. **21. C.** Mechanism real, association real, causal claim not established. Genetic-instrument studies have offered some support without settling the question. **22. B.** This is the chapter's asymmetry: the specific proposition was tested in humans with better tools than any gray-market vial and did not hold. That is evidence against, not absence of evidence.