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WASTING ≥ WEAKNESS

• Type 2 fiber atrophy: Disorders
  • Cachexia: Weight loss > 15%; Systemic disease
    • Paraneoplastic Neuromyopathy
  • Sarcopenia & Aging
  • Disuse
  • Pathology
    • Muscle fiber atrophy: Type 2 > Type 1
      • Early: May be Type 2B > 2A
    • Myonuclear domain: Smaller
• Diffuse fiber atrophy: Type 2 atrophy may be > Type 1
  • Denervation
  • Botulinum toxin
• Endocrine
  • Corticosteroid-related: Also see Myosin loss
  • Hyperthyroidism
  • Metabolic: Testosterone Low
• Other
  • Microgravity ¹¹
  • Toxic: cisplatin
• Prominent wasting + Weakness/Myopathy: Other disorders
  • Congenital myopathies
  • Congenital myasthenic syndromes
  • HIV wasting
  • Dermatomyositis + Vascular Pathology: Perifascicular muscle fiber atrophy

MUSCLE WASTING

• Metabolic changes (Low CG syndrome)
  • Cystine & Glutamine: Low in plasma
  • Glutamate: Low in plasma
  • Glutathione: Low intracellular
  • Urea production: High
• Weight loss
  • Selectively in skeletal muscle
  • Not prevented by aggressive nutrition
• Natural killer cell function: Reduced
• Syndromes with low plasma cystine & glutamine levels
  • HIV: Late asymptomatic stage
  • Sepsis
  • Trauma
  • Bowel disease: Crohn's; Ulcerative colitis
  • Chronic fatigue syndrome
  • Overtraining
• Changes may be reversed by: N-acetyl-cystine (NAC) treatment
• Differs from starvation which has
  • Low urea production
  • Weight loss in most organs

• Time course
  • General
    • Exponential change: Most loss of mass in 1st 14 days of disuse
  • Models: Loss of muscle mass
    • Bed rest: 1 week → 3% to 5%
    • Limb immobilization: 1 week → 5% to 7%
    • Step reduction: 1 to 2 weeks → 2.5% to 4%
    • Denervation
• Atrophy susceptibility
  • Increased: Triceps (7% atrophy in 14 days of disuse); Critically ill patients
  • Resistant: Anterior tibial (2% atrophy in 14 days of disuse)
• Systems & Molecules increased with disuse & atrophy
  • RLF Zinc finger
  • RNF13
  • DEPTOR (DEPDC6)
    • Hub gene of disuse-activated molecular network
  • NCAM
  • Sarcolemma, Extra-junctional
    • AChRs: Immature type with γ-subunit
    • Sodium channels: Na_V 1.8
  • FoxO transcription factors (FoxO1, FoxO3, FoxO4)
    • Upregulate atrophy-related genes
      • Ubiquitin ligases: MuRF1 & Atrogin-1
    • Promote ubiquitin-proteasome-mediated degradation
      • Substrate: Myofibrillar proteins
    • Contribute to: Muscle wasting
• Systems & molecules reduced with disuse
  • Mitochondria
    • Respiratory activity
    • Citrate synthase
    • Related genes: COX4I1; GOT2; ENDOG
  • Insulin-related
    • Sensitivity, Muscle: Reduced
      • Onset: Within 24 hours of disuse
      • Insulin signalling (IRS1; AS160) & GLUT4
    • Insulin-like growth factor 1 (IGF-1)/AKT signaling pathway
  • Muscle protein synthesis
    • Anabolic resistance: Reduced anabolic response to protein feeding
  • Sarcolemma, Extra-junctional
    • AChRs: Mature type with ε-subunit
    • Sodium channels: Na_V 1.7
  • Calpain-3
  • Maf ¹⁰
    • Regulator of fast myofiber maturation
    • Activates promoters of rodent fast muscle-specific genes: Myh4, Actn3, Mybpc2, Ckm
    • Represses: Myogenin, Runx1, Mef2a, Tead4, Foxo1, Foxo3
• Muscle degradative systems
  • General
    • Bulk activity not greatly increased with disuse
    • ‘Targeted’ proteolysis may occur
    • May be more promient with disease-related atrophy
  • Systems
    • Calpains: Cleavage of cytoskeletal/structural proteins
    • Caspases: Apoptosis
    • Autophagy/Lysosomes: Bulk cytoplasm, Long-lived proteins, Organelles
    • Proteosomes: Ubiquitin-tagged proteins; Early induction of UPS-related genes in disuse may impair protein synthetic capacity
• Muscle pathology
• Disorders
  • Sarcopenia
  • Cachexia

Congenital myopathy Severe wasting involves the distal arms & legs. The most distal regions, the hands & feet, are relatively spared

Chronic denervation: Severe, Diffuse

• Severe wasting involves the distal arms & legs including the most distal regions, the hands & feet.
  
• Note atrophy of median (thenar) and ulnar innervated muscles in the hands.
  
• Severe trophic skin changes are present on the legs.

Spiller

Sarcopenia ¹

• Definitions
  • Sarcopenia
    • Features
      • Muscle mass: Reduced
      • Strength or Function: Reduced
      • Body composition
      • Course: Slow progression over adulthood
    • Associations
      • Age: Increased
      • Anatomical: Muscle fiber atrophy or loss
    • Classification
      • Primary: Age- & Sedentary lifestyle- related
      • Secondary: Related to obesity or acute disease
    • Quantitative, Clinical
      • Measure grip strength
      • Males < 60 lbs
      • Females < 36 lbs
      • Muscle mass (kg/m²)
        • Males < 7
        • Females < 5.5
      • Sarcopenia Severe
        • Gait speed (m/sec) < 0.8
        • Timed Up & Go test (sec) ≥ 20
  • Pre-sarcopenia
    • Muscle mass: Reduced
    • Strength or Function: Normal
    • Association: Increased age
  • Muscle biomechanical quality = Strength/Mass
    • Aging: Strength loss > Reduced mass
    • Muscle biomechanical quality: Reduced
  • Muscle Depletion Syndromes (Sarcopenia +)

    Cachexia 3 Definitions Sarcopenia + Weight loss + Low BMI Wasting of Skeletal muscle ± Fat despite nutrition support Disease-related malnutrition with systemic inflammation Quantitative Weight loss ≥ 5% within 6 months 2% + Body mass index (BMI) <20 kg/M2 2% + Sarcopenia Laboratory C-reactive protein (CRP): > 1.0 mg/dL Albumin: < 3.5 g/dL Common with Advanced cancer: Accounts for 30% of deaths Effects Morbidity: Increased and reduces both Tolerance & Responsiveness to treatment: Reduced Cancer Cachexia: Associated with Bone morphogenetic protein (BMP) signaling: Reduced 4 Expression of Noggin (BMP inhibitor) increased in muscle Triggered by Activin A (IHNBA) IL-6 Cancer-mediated factors Proteolysis-inducing factor (PIF; Dermicidin; CCF1) Lipid-mobilizing factor (LMF; ZAG) TNF-α Parathyroid Hormone-like protein (PTHRP; PTHLP) Adipose wasting: UCP1 Anorexia & CNS Proopiomelanocortin (POMC) Cart Prepropeptide (CART; CARTPT)

    Cachexia Starvation Body Weight ↓ ↓ Skeletal   Muscle ↓ → Adipose   Tissue ↓ ↓ Rest Energy   Expenditure ↑ ↓ Inflammatory   Markers ↑ →

    • Sarcopenic-Obesity (SO) ⁶
      • Definition: Co-existence of Obesity & Sarcopenia ⁵
        • Obesity
          • Definition: Body mass or Waist circumference High
          • General frequency: 13%; ~1 billion individuals globally
          • Frequency > 65 years: 35%
          • Related to: Reduced muscle mass & quality
        • Sarcopenia: Clinical, Risks, or Criteria
      • Risks
        • For SO: Increased with age; Especially > 70 years
        • Of SO: Combination of 2 conditions
        • For: Frailty
      • Complications
        • Prognostic for: Increased Disability; Reduced survival
        • Disorders: Metabolic; Cardiovascular; Respiratory
        • Functional disability: Falls; Fatigue; Movement limitation
    • Frailty
      • Definition: Sarcopenia + Weight loss (Unintentional)
    • Dysmobility: Sarcopenia +
      • High fat mass
      • Osteoporosis
      • Falls: In past year
• Sarcopenia: Course
  • Onset age: May begin at 25 years
  • Age 40 years: 10% loss in muscle mass
  • Age ≥ 50 years
    • More rapid decline
    • 15% loss per decade
    • Age 70 years: 40% loss in muscle mass
  • May be reduced, or prevented, by: Physical activity
• Sarcopenia: Associations & Epidemiology
  • Population: ~ 70 million people world-wide
  • Prevalence
    • Healthy, > 65 years
      • Males: 0.5% to 5.3%
      • Females: 1.8% to 13.3%
    • Neoplasm
      • Solid tumor patients: 15% to 74%
      • Cancer, Pre-treatment: 19%
  • Age: Increased frequency/prevalence
    • 60 to 70 years: 5% to 13%
    • > 80 years: 11% to 50%
    • Community dwelling elderly adults: 9.9% to 40.4%
    • Hospitalized adults ≥ 65 years: 46%
  • Sex
    • Female > Male
    • Male-Female muscle quality differences
      • Related to % body fat
  • Geography: Non-Asian > Asian
  • Disability
    • More associated with: Loss of Strength than Mass
  • Predictors of reduced muscle quality
    • Visceral obesity
    • Cognitive executive dysfunction
    • Nerve conduction velocity: Reduced
  • Sarcopenia: Higher prevalence
    • Smoking
    • Chronic obstructive pulmonary disease (COPD): 2x higher
    • Non-independent living
    • Less activity
    • Metabolic syndrome: 3 or more of
      • Obesity: Waist > 102 cm in men & > 88 cm in women
      • Triglycerides: High
      • High-density lipoprotein cholesterol: Low
      • Blood pressure > 130/85
      • Fasting plasma glucose: > 100 mg/dl
    • CAR T-cell treatment ⁹: Associated with fatty acid catabolism
  • Possible association: Fracture risk increased
• Laboratory
  • Motor unit potentials: Amplitudes reduced with sarcopenia
  • MUNE: Motor unit size smaller
  • ACTN3 XX genotype: Gait more slowed with age
  • Serum
    • High: Hypoxanthine, Galactose, Mannose
    • Low: Triethanolamine, Homogentisic acid, α-tocopherol
  • Muscle
    • Morphology
      • Muscle fiber atrophy: Type 2 more than type 1
      • 2B (2X) muscle fibers: Reduced
      • Also see: Aging changes in muscle
    • Mitochondrial ²
      • Age-related: Complex I activity reduced
      • Muscle fiber atrophy-related: Complex I, II ± III activities reduced
    • Senescence/Denervation markers (Rat; mRNA) ⁸
      • Location: In small muscle fibers
      • Molecules: TMEM158 , CDKN1a , CDKN2a
      • Molecular modifications: Alternative splicing, exon inclusion or skipping
    • mTORC1
      • Hyperactivation
      • Sarcopenia driver
      • Upstream activator: DEAF1
• Sarcopenia: Quantitation & Imaging
  • Muscle mass: Dual X-ray absorptiometry (DXA)
    • Measures
      • Appendicular Lean Mass (ALM) / Height²
      • ALM / Body Mass Index (BMI)
    • Muscle Manifestations in Sarcopenia
      • Size: Reduced
      • Fat: Increased
  • Muscle mass: Other imaging methods
    • Bioelectrical impedance analysis (BIA)
    • Computed Tomography (CT)
    • Ultrasound
  • Reduced strength or Physical performance
    • Some patients
    • Handgrip quantitation
      • Males: ≤ 26 to 32 kg (57 to 70 lbs) depending on BMI (24 to 28)
      • Females: ≤ 16 to 21 kg (35 to 46 lbs) depending on BMI (23 to 29)
    • Gait speed
      • Males: ≤ 0.65 m/s to 0.76 depending on height (≤ 173 cm)
      • Females: ≤ 0.65 m/s to 0.76 depending on height (≤ 159 cm)
    • Short Physical Performance Battery (SPPB)
      • Standing & Walking: Tandem
      • Standing & Sitting from Chair

Sarcopenia: Muscle Pathology

H&E stain

ATPase ph 9.4 stain

Microgravity: Muscle ¹¹

• Mass: Rapid reduction
• Fiber sizes: Reduced
  • Both types
  • Especially postural
• MHC1: Reduced expression
• Mitochondria
  • Numbers: Reduced in Type I fibers
  • Oxidative enzyme capacity: Reduced
  • Electron transport efficiency: Reduced
  • ROS production: Increased
  • mtDNA: Stable
• Type I (Slow twitch) fibers: Reduced
• Force production: Reduced
• Satellite cells: Reduced numbers
• Extracellular membranes: Disorganized
• Capillary density: Reduced