Skeletal Muscle as a Dynamic Organ that Orchestrates Whole Body - - PowerPoint PPT Presentation

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Skeletal Muscle as a Dynamic Organ that Orchestrates Whole Body - - PowerPoint PPT Presentation

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European Union Geriatric Medicine Society Nice, France 20-22 September, 2017 Skeletal Muscle as a Dynamic Organ that Orchestrates Whole Body Metabolism Prof. Dr. Josep M. Argils Universitat de Barcelona Spain EUGMS, 2017 Disclosures

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Skeletal Muscle as a Dynamic Organ that Orchestrates Whole Body Metabolism

  • Prof. Dr. Josep M. Argilés

Universitat de Barcelona Spain

European Union Geriatric Medicine Society Nice, France 20-22 September, 2017

EUGMS, 2017

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EUGMS, 2017

Disclosures

  • Danone – Advisory Board
  • Smartfish – Research Collaboration
  • Abbott Nutrition – Research Collaboration
  • Rottapharm – Advisory Board
  • Acacia – Research Collaboration
  • Santhera – Research Collaboration
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EUGMS, 2017

Learning Objectives

  • 1. Provide an overview of the relationship between skeletal

muscle and metabolism

  • 2. Describe skeletal muscle plasticity in response to

environmental and physiological challenges

  • 3. Discuss the clinical implications in muscle wasting

conditions

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SKELETAL MUSCLE

Main reservoir of proteins Glutamine synthesis and storage Regulator of glucose levels

METABOLIC FUNCTIONS

Physical movement Strength Maintenance

  • f posture and

balance

STRUCTURAL FUNCTIONS

EUGMS, 2017

The Muscle and Its Main Functions

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EUGMS, 2017

Average Muscle Mass

38-54% men 28-39% women

40%

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EUGMS, 2017

Argilés, J.M. et al. JAMDA, 2016

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EUGMS, 2017 Newsholme, P. et al. Cell Biochem. Funct., 2003

Antioxidant defense system Cell Proliferation

Glutamine is Mainly Synthesized and Stored in Skeletal Muscle

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EUGMS, 2017

Adapted from Brosnan, J.T., J. Nutr. 2003

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EUGMS, 2017

Skeletal Muscle is a Regulator of Metabolic Homeostasis

Rai et al (2016) Annu. Rev. Physiol. 78:85–107

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EUGMS, 2017

Skeletal Muscle Orchestrates Metabolic Events

Adapted from Fiuza-Luces C et al (2013) PHYSIOLOGY 28: 330–358 Pedersen BK & Febbraio MA (2012) Nat. Rev. Endocrinol. 8, 457–465

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EUGMS, 2017 Argilés, J.M. et al. JAMDA, 2016

Complications of Lean Body Mass (Muscle) Loss

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EUGMS, 2017 Argilés, J.M. et al. JAMDA, 2016

Effects of Ageing and Illness on Muscle Mass

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SKELETAL MUSCLE WASTING

INCREASED BCAA OXIDATION INCREASED PROTEOLYSIS DECREASED PROTEIN SYNTHESIS

DECREASED AA UPTAKE

DECREASED MUSCLE REGENERATION MITOCHONDRIAL DYSFUNCTION/ SR STRESS INCREASED APOPTOSIS EUGMS, 2017 Argilés J.M. Clin. Nutr., 2017

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Skeletal Muscle Wasting Crosstalk

EUGMS 2017

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GUT (malabsorption) Gut-barrier dysfunction Altered ghrelin production Release of inflammatory mediators WHITE ADIPOSE TISSUE (wasting) Increased lipolysis Release of fatty acids Release of inflammatory mediators ? BRAIN (anorexia) Altered pattern of hypothalamic mediators Loss of appetite Hyposmia Hypogeusia LIVER (acute-phase response) Release of acute-phase proteins Hypoalbuminaemia Release of inflammatory mediators ? HEART (cardiac dysfunction) Atrophy Decreased innervation Increased energy consumption Release of inflammatory mediators ? BROWN ADIPOSE TISSUE (thermogenesis) Energetic inefficiency

SKELETAL MUSCLE

(wasting)

BONE (resorption) Osteoclast activation

EUGMS, 2017 Argilés J.M. et al. Nature Rev. Cancer., 2014

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EUGMS, 2017

Skeletal Muscle is Not Just Associated with Contraction

Skeletal muscle as a thermogenic organ

Types of thermogenesis Shivering Non-shivering

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Sarcolipin Promotes Oxidative Metabolism under Conditions of Increased Energy Demand. During muscle contraction, membrane depolarization leads to activation of DHPR/RYR1 complex leading to release of Ca2+ from the SR.

EUGMS, 2017 Pant, M. et al. Trends Endocrinol. Metabol., 2016

Sarcolipin: A Key Thermogenic and Metabolic Regulator in Skeletal Muscle

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Skeletal Muscle as an Endocrine Tissue

EUGMS, 2017

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EUGMS, 2017

Glucose Metabolism Inflammation Brain Function Lipid Metabolism Vascular Function

Karstoft K & Pedersen BK. Curr Opin Clin Nutr Metab Care. 2016

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Functions of Myokines

EUGMS, 2017 Weigert, C. et al. Proteomics Clin. Appl., 2014

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Inflammation

Insulin resistance Low anabolic hormones Low blood flow

Drugs?

EUGMS, 2017

How Do We Address the Underlying Metabolic Dysfunction Leading To Muscle Loss?  Muscle Loss  Muscle Gain

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DRUGS

DRUGS

DRUGS

DRUGS

DRUGS

EUGMS, 2017

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TOXICITY

TOXICITY

TOXICITY

TOXICITY

TOXICITY

EUGMS, 2017

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100

Anti-inflammatory treatment Anti-anaemia treatment Exercise program Nutritional support Best supportive care Anti-tumour treatment Multidisciplinary team Early intervention Diagnostic awareness

Efficacy of Multimodal Therapy for Cancer Cachexia

%

Improved management of cancer cachexia certainly requires a multimodal approach by a multi-disciplinary team and is best commenced earlier rather than later

50 Years of Academic Nutrition Education Norway, Oslo, 2016 EUGMS, 2017 Argilés, J.M. et al. Biochem. J., 2017

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EUGMS, 2017 Argilés, J.M. et al. JAMDA, 2016

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HMB: Ergogenic Nutritional Supplement

Leucine metabolite Grapefruit, alfalfa, catfish

EUGMS, 2017

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EUGMS, 2017

  • HMB is a natural metabolite of the amino acid leucine1
  • Produced in low levels in the body
  • Science behind HMB
  • Originated in the ‘Sports Nutrition ’ world
  • Studied in relation to disease states and older adults for over 15

years2

  • Ca-HMB is Generally Recognized As Safe (GRAS) up to 6 g/day

-Hydroxy--Methylbutyrate (HMB)

  • 1. Nissen SL, Abumrad NN. J Nutr Biochem. 1997;8:300-11
  • 2. Wilson GJ et al Nutr Metab. 2008;5:1 (review)
  • 3. Fitschen, PJ. et al. Nutrition 29.1 (2013): 29-36.

Most referenced dose 3 g/d (Ca-HMB), no safety issues 1,2,3

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Metabolism of HMB in the Body

EUGMS, 2017 Sabourin,PJ and Bieber LL . Metabolism 32.2 (1983): 160-164. Nissen SL, Abumrad NN. J Nutr Biochem. (1997);8:300-11. Walker D et al J. Chromat. B 1040 (2017): 233-238.

0.5-5%

Acetoacetate + Acetyl CoA

~95% - Ketoisocaproate (KIC)

LEUCINE

BCAA transferase BC-Keto acid Dehydrogenase

KIC dioxygenase

Circulates to muscle

10-40% in Urine -Hydroxy- methyl butyrate (HMB)

Cholesterol

HMG-CoA

Mevalonate

Isovaleryl CoA -hydroxy--methyl glutaryl-CoA (HMG-CoA)

-methyl crotonyl-CoA -methyl gluconyl-CoA

HMG-CoA Lyase

HMB-CoA

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Mechanisms

EUGMS, 2017

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‐hydroxy‐‐methylbutyrate supplementation and skeletal muscle in healthy and muscle‐wasting conditions

EUGMS, 2017 Holecek, M. J. Cachexia Sarc. Muscle., 2017

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Developing Muscle Wasting (Atrophy)-Specific Nutritional Approaches

EUGMS, 2017

Objectives

Increase body weight Stimulate food intake Decrease inflammation Decrease energy expenditure Enhance absorption/Gastric emptying Preserve LBM (anabolic + anticatabolic) Enhance QoL Control disease Increase survival

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Take Home Messages

  • Skeletal Muscle:
  • Orchestrates metabolic events
  • Regulates metabolic homeostasis
  • Serves as an important thermogenic, metabolic, and

endocrine organ

Skeletal Muscle as a metabolic organ

  • Skeletal Muscle wasting is associated with morbidity

and mortality

Skeletal Muscle wasting in disease

  • Conventional nutrition is unable to reverse muscle

wasting

  • Use of drugs is associated with toxicity

Nutrition and Skeletal Muscle wasting

  • Combination of nutritional approaches (including

nutraceuticals) with exercise has important potential in treatment of muscle wasting

  • HMB: ↑ body weight, stimulates food intake,

↓ inflammation, and may serve to preserve LBM Nutraceuticals: HMB

EUGMS, 2017