🐻 The Brown Bear Paradox: Surviving Without Muscle Loss

❄️ What is hibernation?

Hibernation is a survival strategy that allows mammals to endure harsh winters by:

• Lowering body temperature
• Reducing metabolic rate
• Decreasing heart rate, oxygen consumption, and neural activity
• Entering prolonged fasting and inactivity

This normally causes severe muscle atrophy in non-hibernators due to an imbalance between protein synthesis and degradation.

💪 Why are brown bears special?

Brown bears (Ursus arctos) hibernate for 5–7 months:

• No food or water
• Minimal movement
• Body temperature drops to ~33.5 °C

Yet, they:

• Lose only 10–15% muscle mass
• Reduce metabolism by 20–50%
• Avoid metabolic diseases common in humans under inactivity

This makes them a biological paradox and an ideal model for studying muscle preservation.

🧪 Seasonal Changes in Bear Blood Plasma

🧬 Proteomics & metabolomics findings

Comparing summer vs winter bear plasma revealed:

• Higher total protein concentration in winter, despite lower levels of many individual proteins → Likely due to dehydration, reduced protease activity, and longer protein half-life
• Strong upregulation of lipid-related molecules:
  • LDL cholesterol
  • Triglycerides
  • Phospholipids
  • Apolipoproteins
  • Serum albumin (fatty acid transport)

🛡️ Immune system shift

• Increase in innate immune components (e.g. lysozyme C, cathelicidin)
• Decrease in adaptive immune proteins (complement, antibodies) → Bears rely mainly on innate immunity during hibernation

🧠 Key Plasma Factors of Interest

🔴 Haptoglobin (HP)

• Increased 4.7-fold in winter
• Binds free hemoglobin, preventing ROS formation
• Likely functions as stress protection, not inflammation

🧪 Sex Hormone Binding Globulin (SHBG)

• Increased ~45-fold in winter
• Regulates hormone bioavailability
• In humans, low SHBG is linked to:
  • Type II diabetes
  • Obesity
  • Cardiovascular disease
  • Muscle weakness → High SHBG may help bears maintain muscle and metabolic health

🧬 Amino acid and nitrogen conservation

Winter bears show higher levels of:

• Glutamine, glutamate, lysine, histidine, proline
• Carnosine, ornithine, acetylornithine

At the same time:

• Methionine sulfoxide (oxidative stress marker) is reduced 5-fold

Despite being anuric and having reduced kidney filtration, bears:

• Recycle urea via gut bacteria → ammonia → reused nitrogen → Preserves protein and prevents muscle loss

🧫 Why Use Bear Serum Experimentally?

• Bear serum contains bioactive factors that:
  • Protect human muscle cells
  • Regulate TGF-β / BMP signaling
• Exact molecules are still unknown
• Goal: identify circulating anti-atrophy signals

🪱 Why C. elegans?

🔬 Model organism advantages

C. elegans is:

• Transparent
• Fast-growing (3–5 days to adult)
• Fully mapped cell lineage
• Genetically tractable
• ~83% of its proteome has human homologs

🧬 Immune relevance

• Lacks adaptive immunity
• Relies entirely on innate immunity → Similar to hibernating bears

🧪 Feeding feasibility

Although worms do not naturally consume blood:

• They can digest human red blood cells
• They survive on serum albumin nanoparticles → Supports feasibility of bear serum exposure

💤 The Dauer State: Worm Hibernation

🧊 What is dauer?

A stress-resistant, non-feeding larval state triggered by:

• Low food
• High population density
• Temperature stress

Key features:

• Halted development
• Thickened cuticle
• Sealed mouth
• Reduced movement
• Months-long survival

🔋 Metabolic adaptation

• Fat and carbohydrate storage
• Resistance to oxidative stress
• Upregulation of:
  • HSP90
  • Superoxide dismutase

If conditions improve, dauers rapidly resume normal development.

🔗 Dauer Signaling Pathways (Highly Conserved!)

Dauer formation is controlled by pathways also central to human biology:

• Insulin / IGF-1
• TGF-β
• TOR (mTOR)
• Steroid hormone signaling
• Sensory input

🧬 daf genes

• Daf-d: cannot form dauer
• Daf-c: form dauer even under good conditions

🍬 Insulin-Like Signaling in C. elegans

🧠 Core components

• Single insulin/IGF receptor: DAF-2
• Downstream cascade:
  • AGE-1 (PI3K)
  • PDK-1
  • AKT-1 / AKT-2
• Central transcription factor: DAF-16 (FOXO)

⚖️ Functional switch

• High insulin signaling → DAF-16 inhibited → growth
• Low insulin signaling → DAF-16 enters nucleus →
  • Stress resistance
  • Longevity
  • Dauer programs

Reducing DAF-2 signaling can double lifespan.

💪 Muscle Structure & Atrophy

🧬 Skeletal muscle basics

• Muscle fibers (myofibers) contain:
  • Sarcomeres
  • Actin (thin) & myosin (thick) filaments
• Contraction depends on:
  • Ca²⁺ release
  • Troponin–tropomyosin shift
  • ATP-driven cross-bridge cycling

🪱 Worm muscle vs human muscle

• Body wall muscle is functionally similar
• Differences:
  • No satellite cells
  • No regeneration
  • 95 mononuclear muscle cells
• Sarcomere organization is conserved

📉 Mechanisms of Muscle Atrophy

Muscle homeostasis = balance between:

• Protein synthesis (mTOR, AKT, SGK1)
• Protein degradation:
  • Ubiquitin–proteasome system
  • Autophagy
  • Calpains

🧠 FoxO as a master regulator

• Activates catabolic genes
• Suppressed by AKT/SGK1

🧬 Evidence from C. elegans

• Starvation induces muscle atrophy
• clp-4 (calpain) mutants:
  • Lose only ~21% muscle size
  • vs ~44% in wild type → Calpains actively promote muscle degradation

🎯 Big Picture Takeaway

This project integrates:

• 🐻 Bear hibernation biology
• 🧪 Blood-borne protective factors
• 🪱 C. elegans as a scalable in vivo model
• 💪 Muscle and mitochondrial health

The ultimate goal is to uncover circulating, evolutionarily conserved mechanisms that protect muscle during extreme inactivity—knowledge with major implications for aging, disease, and space biology 🚀