Chapter 16 — Exercises

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

Items marked † are extended: they take longer, have no single correct answer, or ask you to defend a position rather than retrieve a fact. Work them in writing.

No answers are provided here. Several items have deliberately contested answers; where a question asks what you think, the reasoning is the assessed part, not the conclusion.

Section A — How muscle grows

A1. State the net protein balance equation in your own words, and name one intervention that acts principally on the synthesis side and one that acts principally on the breakdown side.

A2. A friend says, "Muscle growth is basically about protein intake." Using §16.1, identify what is right about that and what is missing. Rank the inputs to hypertrophy by the size of their contribution and justify the ranking.

A3. Explain why bed rest, limb immobilization, and spaceflight all produce muscle loss. What single term in the balance changed in each case?

A4. Define hypertrophy and hyperplasia. State which one dominates in adult humans, and explain in one sentence why that distinction matters for interpreting the Belgian Blue.

A5. † The chapter says "resistance training is the dominant intervention and no peptide substitutes for it." Construct the strongest possible objection to that claim — the version a well-informed skeptic would offer, not a strawman — and then answer it.

Section B — IGF-1, mecasermin, and IGF-1 LR3

B1. In two sentences, describe the relationship between GH and IGF-1. Where is most circulating IGF-1 produced, and in response to what?

B2. What fraction of circulating IGF-1 is free? Explain what the IGF binding proteins do to half-life, distribution, and activity.

B3. Explain why a lab report of "total IGF-1" is a less informative number than people assume.

B4. What is mecasermin approved for? Write the indication precisely enough that someone could not generalize it by accident.

B5. Mecasermin's labeling carries a prominent hypoglycemia warning. Explain the structural reason, referring to what IGF-1 resembles.

B6. † IGF-1 LR3 was engineered to reduce binding-protein affinity. Write a paragraph arguing that this is a clever solution to a real pharmacokinetic problem, then a second paragraph arguing it is the deliberate disabling of a control system. Say which paragraph you find more persuasive and why.

B7. † IGF-1 LR3 originated as a cell-culture reagent for industrial bioprocessing. Explain what, if anything, that provenance tells you about its suitability for use in humans — and be careful to distinguish what it establishes from what it merely suggests.

Section C — Myostatin and follistatin

C1. Myostatin is described as a "brake." Explain what that metaphor captures about the architecture of muscle growth regulation, and name one thing the metaphor obscures.

C2. Trace myostatin's signaling path from ligand to nucleus, naming the receptor and the intracellular messengers.

C3. Name two close relatives of myostatin that signal through the same type II receptor, and state one physiological process each is involved in. Explain why their existence creates a drug-design trade-off.

C4. List the four natural loss-of-function observations described in §16.3 (mice, cattle, dogs, humans) and state, for each, what kind of evidence it is — experimental, observational, genetic, case report.

C5. Follistatin binds more than myostatin. Name at least three of its targets and explain why breadth of inhibition is a liability rather than a bonus.

C6. Follistatin is roughly 35–40 kDa and glycosylated. Using Chapter 1's framework, explain why those two facts together make gray-market product identity a serious problem.

C7. † Someone cites the follistatin gene-therapy trials as support for an injectable "follistatin-344" product. Write a short, non-condescending reply explaining why the citation does not transfer. Assume your reader is intelligent and already invested.

Section D — The trials, and mass versus function

D1. State the central finding of the myostatin-inhibitor programs in muscle disease in one sentence, using the words mass and function.

D2. Distinguish mass, strength, function, and independence. Give one standard measurement for each.

D3. Give two distinct mechanistic reasons why lean mass could rise on a scan without contractile capacity rising proportionally.

D4. Explain the concept of a validated surrogate endpoint. What specifically would have to be shown for lean mass to be a validated surrogate for physical function?

D5. Explain why regulators require functional co-primary endpoints in muscle-wasting indications. Frame it as a lesson learned rather than as bureaucratic caution.

D6. In DMD specifically, two post-hoc explanations are offered for why myostatin blockade underperformed. State both, and then state why "post hoc" is a caveat rather than a dismissal.

D7. † Write the paragraph that a sponsor's press office might have written about a trial that increased lean mass and did not improve function. Then annotate your own paragraph, marking every place where a surrogate is doing the work of an outcome.

D8. † §16.6 argues that ordinary training experience makes the mass-equals-function assumption harder to notice. Reconstruct that argument in your own words, then test it: describe one personal or observed experience that fits the argument and one that resists it.

Section E — Rating practice

For E1–E4, write a full four-line 📊 Evidence Rating block: claim (with population and endpoint), rating, one-sentence reason, and what would change it.

E1. "Mecasermin restores normal adult height in children with severe primary IGF-1 deficiency." (Note the endpoint carefully — it is not the one the chapter rated.)

E2. "IGF-1 LR3 accelerates recovery between training sessions in healthy resistance-trained adults."

E3. "Myostatin inhibition preserves ambulation in boys with Duchenne muscular dystrophy."

E4. "Follistatin-344 increases lean body mass in healthy men who lift weights."

E5. † Two of the chapter's four ratings are ❌ and one is ⚠️, yet the chapter argues the ⚠️ claim is in a worse position than one of the ❌ claims. Explain how that can be true without the rating system being broken. Then propose one concrete improvement to the system that would capture the distinction — and identify what your improvement would cost.

Section F — Dossier: Field 6

F1. Write out the six sub-fields of Field 6 from memory, then check them.

F2. Complete Field 6 for one peptide already in your dossier that is not discussed in this chapter. Identify which of Case A, B, or C it falls into.

F3. Find a claim — from a clinic's website, a supplement label, a podcast, a paper's abstract — where the reported endpoint is a surrogate and the asserted benefit is an outcome. Write out both, side by side, and name the unstated arrow.

F4. † Case A and Case C both often end at ❌. Write two paragraphs explaining to a reader of your dossier why the difference between them matters anyway, and what a person should do differently depending on which one they are looking at.

Section G — Synthesis and transfer

G1. Chapter 8 §8.8 and this chapter's §16.6 report opposite-looking results. State the single principle they share, in one sentence, without using the words "surrogate" or "endpoint."

G2. Chapters 14 and 15 established that "raises GH/IGF-1" is a surrogate claim. Build the full chain from a secretagogue to independent living, naming every link, and count the unvalidated arrows.

G3. † State the cancer question about chronic IGF-1 elevation in exactly five sentences: one for the mechanism, one for the epidemiology, one for the confounding, one for each of the two natural experiments. Do not overclaim in either direction. Then remove one sentence and describe what is lost.

G4. † A close friend tells you they have been offered IGF-1 LR3 by a clinic and asks what you think. Write what you would actually say — not a lecture, not a refusal to engage. Identify the two or three things that would matter most to get across in a real conversation, and what you would ask them before saying any of it.

G5. † Design, on paper, the trial that would move the healthy-adult performance claim from ❌ to something else. Specify population, comparator, randomization, blinding, duration, primary endpoint, and how you would verify drug identity. Then state honestly why the trial you designed is unlikely to be run.

G6. Reread your Chapter 1 dossier entry for anything in this chapter's family. Has your confidence number changed? Write one sentence on which direction it moved and what moved it.