AMPK Explained: MOTS-c vs ATX-304 vs SLU-PP-332 | Mitochondria, Metabolism & Energy Signaling

AMPK is one of the most important metabolic regulators in human biology — acting as a master energy sensor that links exercise, fasting, mitochondrial function, and metabolic resilience. In this deep-dive video, I explain how AMPK activation works, why it matters for metabolism and aging, and how three well-studied research compounds — MOTS-c, ATX-304, and SLU-PP-332 — intersect with the AMPK pathway through very different biological mechanisms. This discussion focuses on energy sensing, mitochondrial signaling, and cellular adaptation to metabolic stress, not on trends or hype. In this video, we cover: • What AMPK actually does at the cellular level • How AMPK signaling connects to NAD⁺, SIRT1, PGC-1α, and mitochondrial biogenesis • Why where a compound acts in a pathway matters more than simply “activating AMPK” • The key animal and mechanistic studies behind MOTS-c, ATX-304, and SLU-PP-332 • What we know — and don’t know — from current research This is a science-first discussion grounded in published literature and biological pathways. Educational purposes only. Key publications discussed: (links below ⬇️) MOTS-c (mitochondrial-derived peptide) Increased expression of the mitochondrial-derived peptide MOTS-c in skeletal muscle of healthy aging men is associated with myofiber composition PMID: 32182209 The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance PMID: 25738459 MOTS-c reduces myostatin and muscle atrophy signaling PMID: 33554779 MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis PMID: 33473109 MOTS-c functionally prevents metabolic disorders PMID: 36677050 ERR agonists and mitochondrial gene regulation (SLU-PP-332 pathway) A synthetic ERR agonist alleviates metabolic syndrome PMID: 37739806 Targeting ERRs to counteract age-related muscle atrophy associated with physical inactivity: a pilot study PMID: 40692696 Synthetic ERRα/β/γ agonist induces an ERRα-dependent acute aerobic exercise response and enhances exercise capacity PMID: 36988910 Direct AMPK activation (ATX-304 / O304 class) AMPK activator ATX-304 reduces oxidative stress and improves MASLD via metabolic switching PMID: 40197369 AMPK activator O304 improves metabolic and cardiac function, and exercise capacity in aged mice PMID: 34795407 Pan-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and patients with type 2 diabetes PMID: 29925691 Important Note This content is for educational and scientific discussion only. It is not medical advice and does not discuss human use, dosing, or treatment. If you enjoy deep dives into metabolism, mitochondria, and longevity biology, consider subscribing for more pathway-focused content. 0:00 Intro: Why AMPK Matters 1:10 What Is AMPK? The Cell’s Energy Sensor 3:00 MOTS-c: Mitochondrial Stress & AMPK Activation 5:45 ATX-304: Direct AMPK Activation 8:10 SLU-PP-332: Mitochondrial Gene Expression 10:10 Final Takeaways FOLLOW & CONNECT Website: https://www.kristisawicki.com/ Instagram: https://www.instagram.com/drkristi.sawicki/ TikTok: https://www.tiktok.com/@kristisawicki? Substack: https://substack.com/@drkristisawicki? Linktree: linktr.ee/kristi.sawicki