What Constitutes Hypertrophy Mechanistically

Layne lists myofibrillar, sarcoplasmic, mitochondrial, and fluid contributions to fiber growth.

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How do muscles actually grow — and what really matters for hypertrophy?

In this episode, I break down muscle growth from the ground up, starting with muscle structure and working all the way through the practical training variables that actually drive hypertrophy.

We cover how muscle fibers are built, why muscle cells are uniquely multi-nucleated, and how satellite cells and myonuclei influence growth potential and long-term adaptations (including the concept of “muscle memory”). From there, we dig into how resistance training shifts net protein balance, why muscle protein synthesis and breakdown both rise with training, and why hypertrophy is often delayed when people first start lifting.

A major focus of this episode is mechanotransduction — how mechanical loading from resistance training is converted into chemical signals that stimulate muscle growth. We unpack what we know (and don’t know) about mTOR signaling, phosphatidic acid, kinase pathways, and why mechanical tension is the primary driver of hypertrophy.

From there, the episode gets highly practical. We break down:

• Why proximity to failure matters more than load

• How volume really works (and why “dose-dependent” doesn’t mean linear)

• The role of training frequency and how to distribute volume

• Why stretch and lengthened positions matter for growth

• Load and rep ranges for hypertrophy vs strength

• Exercise selection, machines vs free weights, and compound vs isolation lifts

• Rep tempo, intensity techniques, and what doesn’t meaningfully affect growth

• Why systemic hormone spikes from training don’t predict hypertrophy

I close with clear, evidence-based takeaways you can actually apply: how hard to train, how much volume most people need, when failure makes sense, how to structure exercises, and how to prioritize effort, recovery, and adherence over gimmicks.

If you want a science-based framework for building muscle — without myths, hype, or unnecessary complexity — this episode lays it out step by step.

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