Sarcopenia: Exercise, Nutrition and Beyond

Hector Lopez, MD, CSCS, MS(c)Physical Medicine and Rehabilitation

RIC-Rehabilitation Institute of Chicago

Northwestern University School of Medicine

Co-Founder: Physicians Pioneering Performance, LLC

Northeast Spine and Sports Medicine, PC.

Outline Definition/ Epidemiology/ Scope What’s in a name? “Players”/ Contributing factors

Intrinsic Muscle cellular/Molecular signaling/

Neuromuscular changes Cytokine/ Immunologic Endocrine/ Metabolic (Systemic/ Cell) Nutritional (Anorexia/Extrinsic and

Responsiveness/Intrinsic) Oxidative Stress Physical Activity (Bidirectional-

Perpetual Cycle) Atherosclerosis/ PVD Partial Role of Apoptosis?

Outline (cont.) Cachexia/Wasting vs. Sarcopenia of

Aging

Role of Supplements/Nutritional Strategies

Exercise Strategies

Pharmacologic Adjuncts

On the Horizon

Sarcopenia Age-related, involuntary loss of muscle

mass, strength and function

3-8% loss of muscle mass per decade after 30, steeper after 60

Sarcopenia + Obesity = “fat-frail”

Fundamental cause of disability, functional dependence, falls, worsening outcome from other illness/disease [Baumgartner RN et al. 1999; Morley JE et al. 2001]

Sarcopenia Prevalence: 35% - 45% of Older US

population (>65)

Modifiable public health care cost/ burden – over $60 billion and escalating with senior demographic [Janssen I et al. 2004]

DEXA and RSMI for estimating

prevalence [Wang Z et al. 1996; Proctor DN et al. 1999]

Solution to this problem: Multi-disciplinary approach vis a vis Performance Nutrition/ Fitness Professionals

What’s in a name? Sarcopenia a misnomer?

“Sarco” (G. sarx = flesh)

“Penia” (G. penia = poverty/ deficiency)

“Myo” (G. myos = muscle)

I propose “Myopenia”

“Players” in Sarcopenia Intrinsic Muscle (Molecular and Cellular)

Reduced muscle cell #, SRetic volume Ca++ handling

Myonuclear centralization, reduced plasma membrane potential/sensitivity, intra-myocellular

Age-related decline in basal/resting MHC, and mixed muscle protein synthesis

Disproportionate atrophy of type IIA muscle fibers ↓ IGF-1/PI3K/Akt signalling ↑FOXO(forkhead

fam TFs), MAFbx/Atrogin (muscle atrogin F-box

containing ubiquitin ligase) and MuRF1 (muscle ring finger ub-ligase)

↓Satellite Cell activation/ signaling for differentiation, recruitment and proliferation (less MHC and CK expression)

“Players” in Sarcopenia Neuromuscular

Decreased in distal more than proximal MU populations

↓ # and NCV of α-motor neurons (esp. the larger, faster conducting FF and FFR type)

↓ Rate firing, Rate coding ↑ Peripheral sprouting (more distal) ↓ Neuromusc End-plate area/ folds

Cytokine/ Immunologic Still many gaps in our knowledge

do know altered cytokine “milieu” w/ aging;

small change in protein catabolism/ anabolism balance X many years = large BComp change

“Players” in Sarcopenia Cytokine/ Immunologic (cont.)

↑ tIL-6, IL-1R, systemic TNF, possible relative inc tIL-1 [Roubenoff R et al. 1998]

IL-6 is moderate catabolic cytokine, also functions as regulator of TNF and IL-1R

IL-6 suppresses extensive inflammation in elderly AT the EXPENSE of ….skel muscle proteolysis, AA oxidation/ mobilization

Cytokines confer a “permissive” effect to ‘foster’ sarcopenia with low-grade systemic inflammation as a catabolic backdrop for –’ve muscle protein balance

“Players” in Sarcopenia Endocrine/Metabolic

Cellular: ↓Glycogenolytic, Glycolytic capcity,

Phosphagen circuit (↓ATP, CrP), TCA cycle enzymes, Mitochondrial Resp Chain Fxn/ mtDNA and mt-protein synth VO2max decrement

Altered protein metabolism (basal MHC and sarcoplasmic protein synthesis, and mt-Protein synthesis)

“Players” in Sarcopenia Endocrine/Metabolic

Systemic: Testosterone- 60% over age of 65

are hypogonadal (Andropause)

↓DHEA- (Adrenopause) GH/ IGF-1 axis- gradual decline w/

aging [Lamberts SW et al. 1997]

↓ Autocrine/ Paracrine MGF/ FGF/ PDGF peptide growth factors

Insulin Resistance at Skeletal Muscle (blunted downstream signaling for protein synthesis in elderly vast diff in anabolic response to mixed meals young vs. elders) [Rasmussen BB et al. 2006]

“Players” in Sarcopenia Nutritional/ Intrinsic

Endogenous whole body and muscle protein response to carb-protein (mixed meal feeding) is perturbed:

• Insulin appears to abrogate and impair anabolic response of muscle protein to the + effect of AA alone [Dreyer H et al. 2005; Volpi et al. 2000; Rasmussen et al. 2006]

↓GH pulse magnitude in post-absorptive state

“Players” in Sarcopenia Nutritional/ Extrinsic

Anorexia of aging: food intake requires complex integration of Periph and Central signals

↓ fundal relaxation of stomach ↑ antral stretch of stomach ↑ CCK release to given fat load Leptin increases in ♂ throughout

lifespan; in ♀ decline in old age Anorectic cytokines (CilNF, TNF,

etc.) Central regulation-neurotransmitters,

endogenous opioids, NPY, endo-cannabinoid/ vanilloid systems

Cross-talk in neurochemistry with Mood

“Players” in Sarcopenia Oxidative Stress (particularly mt fxn)

ROS/RNS generated in muscle oxidative stress

Metabolic stressors (Steady state and Exercise), inflammatory stressors, co-existing disease

~65 yoa- threshold age for imbalance in antioxidant: oxidant: biomolecule homeostasis?

NF-κB activation and inflammatory cascade propagation

↓nNOS activity

Physical Activity (lack thereof): Quality and Quantity Both factor and consequence of Sarcopenia Bidierctional nature w/ “self-perpetuating”

vicious cycle• Feedback and Feedforward Loops

“Players” in Sarcopenia Atherosclerosis/ PVDz:

Role of microcirculation/ endothelial health in regulating nutrient delivery, anabolic and catabolic stimuli

Role of Apoptosis (individuality) Cumulative ultra-structural,

biochemical damage to SReticulum and mitochondria Caspase enzyme cascade

Variable depending on co-morbidities/ genotype

Players in Sarcopenia“Chicken or the Egg”

Sarcopenia ↓ Physical Activity

-Insulin Resistance-Neuromuscular Maladapt.-Cytokine Activity-↓ Type IIa muscle fiber

-↓ Anabolic Hormone-↓ Response to Exercise/ Nutritional Stimuli- Oxidative Stress- Anorexia

BIDIRECTIONAL

Sarcopenia of Aging VS. Cachexia

Cachexia is a more aggressive, involuntary general weight loss (lean body AND fat mass) occurring SECONDARY to a chronic disease.

Cancer, COPD, HIV/AIDS, CHF, Rheumatoid Arthritis most common for cachexia/wasting

Nutritional StrategiesBig Picture Basics: Maximize whole food nutritional platform

Protein is “King” in the sarcopenic population

Current RDI is 0.8g/Kg/day Some data on benefit of 1.6g-2.0g/Kg/day

Omega-3 lipids are “Princes” (higher length DHA/EPA)

Immuno-modulation, systemic inflammation, proteasome inhib, eicosanoid milieu, insulin sensitivity, mood/sleep quality, etc. [Calder PC, 2002; Fearon et al. 2003; Smith et al. 2004]

Nutritional Strategies “CHRONO-Nutrition”

TIMING, TIMING, TIMING! (yes, it works for “grandma” and “grandpa” too)

Nutritional Periodization for Seniors

“Rational Polysupplementation” BCAAs (esp. Leucine):

“Anti-anorectic” action via hypothalamic serotonergic modulation

• Anorexia assoc w/ deranged Trp/5-HT metabolism; Trp/LNAA ratio predict brain 5-HT concentrations [Rossi et al. 1986; Cangiano et al. 1996]

Promoting Protein Synthesis

Inhibiting Proteolytic Pathways [Ventrucci et al. 2004; Paddon-Jones et al. 2004; Poon et al.]

Nutritional Strategies HMB (and Arg, Lys, Gln) [May et al. 2002; Flakoll

et al. 2004]

Protein vs. EAA vs. Prot-NRG Kinetics (that TIMING thing again) Feeding Pattern

Leucine “fortification”

Specific EAA profile (over-weighting in certain “high impact” drug-like aminos)

Creatine [Brose et al. 2003]

MVI/ MMI

Strategic Kcal/NRG Restriction vs. a “Metabolic Mimetic”?

Nutritional StrategiesHonorable Mention Anti-Ox supplementation

Potential to improve exercise tolerance, insulin sensitivity, modulate inflammation

KIC

Beta-Alanine

Endocannabinoids

Structured Lipids/ other PPAR-alpha/delta agents

L-Carnitine (PLCAR/ ALCAR)

Exercise Strategies Targeting FFR motor units Augment Type IIA (FOG)/ muscle fiber

CSA Role for occasional “Concentric emphasis”

sessions for insulin action/sensitvity [Asp S et al. 1996; Kirwan JP et al. 1992]

Resistance Training The MOST effective long-term intervention

for attenuating or preventing sarcopenia [Frontera WR et al. 1988; Charette SL et al. 1991; Lexell J et al. 1995; Vincent KR et al. 2002]

Cadence (3-6s eccentric, 1-2s concentric progress to more explosive concentric)

High yield compound, multi-joint exercises Important to account for individual’s training

history, limitations, med/surg history

Exercise Strategies Resistance Training (cont.)

Training parameters for exercise prescription proper dose response

Volume, Load/ Intensity (70%-95% 1-RM), Frequency, Duration to (Sarcoplasmic vs. Myofibrillar hypertrophy)

Periodize the loading parameters and progressions to stay ahead of the “adaptational curve” (2-5 week intervals)

Modify exercise selection, parameters, program design to “tailor” the exercise Rx long-term

• Purposeful, Goal-directed

Exercise Strategies Resistance Training (cont.)

Strength training using 70-95% of 1RM loads and Eccentric emph

Ultrastructural damage to contractile proteins/ myofibrillar proteolysis [Evans WJ et al. 1991; Frontera WR et al. 1988]

Autocrine/Paracrine IFG, FGF, and PDGF ↑ prot synth and satellite cell activation [Yamada S et al. 1989; Yan Z et al. 1993]

Decreased Acute Phase Response to RT in elderly (↓CK release, ↓PMN mobilization, IL-1β) and PGs/eicosanoid response ↓ Adaptation and Remodeling [Goldberg AL et al. 1988; Cannon JG et al. 1994]

Exercise Strategies Cardiovascular Conditioning/ “Energy

Systems Training” More critical in the Sarcopenic-Obese population More “permissive” to improve recovery ability

and metabolic alterations from HI-RT (i.e. insulin sensitivity, glucose tolerance)

Appropriate Modality for individual Establish “Base” for ↑ Work Capacity (CO)

Cardiorespiratory testing (likely “higher risk” –ACSM class B, or C)

Wider range of peak HR (50-80%) Monitoring becomes even more useful “Steady-state” and “IR-HIIT” protocols after

established good base scaled down appropriately

Exercise Strategies Other Modalities/ Considerations

FES and “Hybrid”/Dynamic-FES assisted “violates” Henneman’s Size Principle [Mahoney et al. 2005]

Whole body vibration/ “Power plate” options to provide different overload in CKC exercises

Role for VOT/ Acute Focal Ischemia

“Multi-Compound Complexes”

Develop strength and function in multiple planes

Biomechanical/ Functional Anatomy considerations to reduce injury risk and improve training adaptations

Adjunctive Medical Treatment Anabolic Hormone therapy

AAS (oxandrolone, nandrolone, testosterone esters) SARMs (Selective Androgen Receptor Modulators;

up and coming!) Peptides (hGH, hGH secretagogues)

• Dose/Duration Response SSRI/SNRIs

“3 birds with one stone” Mood, Sleep, and Appetite

Examples: Mirtazepine, Trazodone Megestrol Acetate

Edema and disrupting the HPA axis (A bad thing!) Insulin Sensitizers (Biguanide class Metformin Vs. TZD-

PPAR agonists) Limit (caution with) NSAID use affects muscle

protein metabolism following eccentric/resistance exercise [Trappe TA et al. 2002]

Adjunctive Medical Treatment GHRH and IFG-I/IGFBP-3 complex as

safer alternatives to GH [Khorram et al. 2000; Vittone et al. 2001;Sullivan DH et al. 1998]

Testosterone replacement generally better tolerated, and more effective in improvement of global functional status outcomes, mood states, and strength (Prostate CA concerns overstated)

Methodologic problems in many previous studies; should adjust for circulating T [Ferrando AA et al. 2002]

General Principles in Sarcopenia Management

(Mx) Nutrition and Exercise Remain the

CORNERSTONE of Tx and Px

Resistance exercise confers an amplified anabolic response (MPS) from exogenous AA +/- Insulin

Maximize skel muscle mass during young adult into middle age, to provide reserves as buffer to catabolic stressors

Likely a “threshold” lower limit amount of skeletal muscle, beyond which see multi-organ system dysregulation

General Principles in Sarcopenia Mx

Tailored EAA w/ precise AA profile (e.g. overweighted in Leu, Lys, Phe, Met, etc.)

“Medicine is a science of uncertainty and an art of probablility”

-William Osler

Advances in Medicine, Nutrition, and Exercise Science will elucidate previous “uncertainties”…only to open another “abyss of uncertainty”

Salient Points Sarcopenia

major cause of disability and functional decline

imposes a modifiable economic burden w/ Health Care costs

Multifactorial in origin, thereby requires a multidisciplinary approach

To optimize risk/benefit regimen focused on nutrition and exercise w/ potential for structured, supervised anabolic Rx

Focus on High-Intensity/Load PRT (relative) to stop or reverse Sarcopenia

Salient Points Modify Protein and Carb intake to fit the exercise

needs/ goals of a particular day Consider on CV/NRG-sys days: Increased total

protein & carb (Pro:1.2g -1.6g/Kg bodyweight); EAA “peri-workout”; CHO/ BCAA/ Leu/ intake throughout

capitalize on increased gluc tolerance/insulin senstivity; limit AA oxidation/catabolism

Consider on Prog-Resistance Training days: (Pro: 1.0g – 1.6g/ Kg/day) with preference to “pulse” midday; CHO/Pro/healthy MUFA/PUFAs; high ‘anabolic efficiency’ EAA supplement “flanking” peri-wkt and throughout the recovery period; Leucine “fortification”

facilitate skeletal muscle remodeling; support protein anabolism

Salient PointsSalient Points Whey over Casein (in supplement); EAA

over Balanced AA; Animal over Vegetable

“CHRONO-Nutrition”: ‘Pulse’ feeding pattern w/ 65%-70% daily intake midday (e.g. flanking the exercise session), 10%-15% of highly efficient EAA/protein in am and pm

“Rational Poly-supplementation”: Leucine and BCAA ‘enriched’ or ‘fortified’ protein

feeding/ EAA

EPA/ DHA/ functional lipid supplementation

Creatine w/ different dosing regimens (when and if more data becomes available)

ß-alanine + Creatine + Leucine/BCAA + EAA? (more data needed)

Salient PointsSalient Points “Rational Poly-supplementation” (cont.):

MVI/MultiMin and comprehensive, low-dose, frequently dosed Antioxidant supp

2nd tier- β-ala, naturally occurring PPAR modulators, Carnitines, etc. (as apporpriate case by case scenario)

Medical management (where appropriate): Anabolic hormone Rx, Mood/Appetite

agents Molecular targets as they become

available

Note: Many of these nutrition/suppl strategies have yet to be studied using larger, RCTs in healthy, elderly population

Anabolic vs. Catabolic Factors in Sarcopenia

-Testosterone

-IGF/ MGF/ PDGF/ NGF

-Insulin Sensitivity

-Structured Physical Activity/RT

-Adequate Protein/NRG intake/ metabolic response

-IL-6

-Ubiquitin-Proteasome/Caspases

-TNF-

-tIL-1

-Cent/Periph Anorexic Sig

-Atherosclerosis (microcirc)

-Decreased Motor Neuron fxn

-Dec response to key Nutrients/ Hormones

CatabolicCatabolic

AnabolicAnabolic

Immune System

Immune System

Endocrine/MetabolicEndocrine/Metabolic

MusculoskeletalSystem

MusculoskeletalSystem

NeuralsupportNeuralsupport

•Vit D/ Ca++/PO4/Mg

•Protein

•EAA/ BCAA/ HMB/ KIC

•Creatine

•Functional Lipids

•Antioxidants

•Β-Alanine

•Chondro-protective

•7-keto-DHEA

•Creatine

•Acetyl-L-Car

•(other Aminos)

•Antioxidants

•Funct Lipids

•Phosphatidyl Serine

•Protein•Gln, Arg, BCAA•Vit D•Antioxidants•Funct Lipids

•As Below•ALCar/ PLCar•Insulin Sensitizers (R-ALA, + chiro-inositol,Cinnamon extract, etc.)

Neural Support

Immunemodulation

Muscle Protein synthesis

Bioenergetic Substrates

Muscle Protein catabolism

Myogenic GF &Satellite Cell

Activation

Systemic/ Local Inflammation

Plasma Membrane

Support

Multiple Pathways for Augmenting the Training Effect and Performance Adaptations

from a Complementary Approach

On the HorizonOn the Horizon Integrating molecular, pharmacologic,

exercise, and nutritional disciplines Biomolecular computing, nano-technology

applications Nutritional/ Exercise/ Pharmaco- Genomics

(Biomics tech)• Truly establishing “tailored, precise customizatio

n” in Exercise, Nutri/Supp, Molecular targets/Pharma Rx

• “Physiatric” Genomics (Applied Exercise, Nutrition, Meds, Rehab based on genomic data for optimizing fxnl capacity, performance, and QOL temp/perm disabled

Seamless Fusion of Medicine, Performance nutrition, Athletic performance, and Wellness (My vision of “FitnessMD-Integrated Medical Fitness model”)

On the HorizonOn the Horizon FAMuSS study (implications for sports

performance, health and sarcopenia)

Exercise, Nutritional and Pharmaco-Genomics/Proteomics

Nascent stages Not yet changing Mx/Tx (recs benefit

the masses despite SNPs and SNP frequency)

May alter ‘aggressiveness’ of Mx/Tx (management/ treatment)

Next Frontier brings “precise customization” w/ molecular targets, nutrition, and exercise

To learn more or ask a question, click here to contact Dr. Lopez at

www.drhectorlopez.com

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