Endocrine properties of skeletal muscle

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Endocrine properties of skeletal muscle
Josef Brandauer Joslin Diabetes
Center josef.brandauer_at_joslin.harvard.edu
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Lecture overview

• Endo-/para-/juxta-/autocrine signaling
• Classic and novel hormone-secreting organs
• Protein secretion from skeletal muscle
• Interleukin-6 (IL-6)
• Retinol-binding protein 4 (RBP4) a novel
  myokine?

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Endocrine signaling
Endocrine vs. exocrine Endocrine ductless,
vascular, intracellular vacuoles/granules storing
hormones Exocrine ducts or hollow lumen much
less vascularized (salivary gland, sweat glands)
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Other -crine signaling
Paracrine Target cell is close to
signal-releasing cell E.g. Allergic response,
scar formation, blot clotting, etc. Juxtacrine
requires physical contact between two
cells.E.g. Notch signalling Autocrine
secreting cell target cell E.g. Monocytes
(IL-1)
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Hormones
Hormao Gr., to set in motion First use of
hormone Description of secretin, Bayliss and
Starling, 1902
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Classic endocrine glands
Hypothalamus Thyrotropin-releasing hormone ?ACTH
(pituitary) Pituitary TSH, GH Thyroid
Triiodothyronine BMR, catecholamine sensitivity,
protein synthesis Adrenal medulla
Norepinephrine, epinephrine Pancreas insulin,
glucagon Liver IGF-1
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Novel endocrine glands
Heart ANP, BNP blood pressure
regulation Adipose tissue leptin, adiponectin,
etc. satiety, insulin sensitivity,
etc. Skeletal muscle Interleukin-6, others?
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Protein secretion from skeletal muscle
What purpose could this serve? -- Communicate a
change in skeletal muscle environment to other
tissue(s) -- Which change(s)? -- Which
tissue(s)?
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Interleukin-6 (IL-6)
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Interleukin-6 (IL-6)
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Interleukin-6 (IL-6)
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IL-6 before after hindlimb contraction
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Retinol-binding protein 4 (RBP4)
Adipose-tissue G4KO animals are IR in vivo in
vitro glucose transport is not affected
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(s)RBP4

• RBP4 occurs in serum as a tetramer with retinol
  and transthyretin, the carrier protein for
  thyroxine
• AT mRNA and serum protein levels are increased in
  adipo-G4KO mice
• sRBP4 is elevated in other obesity/diabetes
  models (ob/ob, HFD, etc.)
• responsive to TZD treatment (AT mRNA, serum)
• RBP4-/- animals are more insulin sensitive than
  WT control.
• RBP4 injection impairs IRS-1 associated PI3k
  activity in skeletal muscle

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Connection between exercise and sRBP4

• Vitamin A (retinol) levels increase acutely with
  endurance exercise known since the 1950s.
• ? does this imply that sRBP4 is also increased?
• ?can acute rodent treadmill exercise, or in vitro
  contraction, function as a model?

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Acute exercise increases RBP4 in SD rats
AU, arbitrary units Sed, sedentary, Exer.,
exercise 60 post, 60 min after exercise. (N
indicated in bars).
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Where does the exercise-induced increase in sRBP4
originate?

1. Liver
2. Adipose tissue
3. Other tissues?

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Acute exercise does not transiently induce RBP4
mRNA in liver
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or visceral fat
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but
acute exercise transiently increases RBP4 mRNA
in gastrocnemius muscle
Additionally, muscle-specific hRBP4 transgenic
animals show an interesting sRBP4 pattern
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Soooo..

• is RBP4 a myokine?

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• What does an individual muscle fiber show?

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Retinol-binding protein 4 (RBP4)
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Conclusion I

• Acute exercise-induced increases in sRBP4
  concentration are likely a result of increased
  skeletal muscle gene expression and RBP4
  secretion
• Liver and adipose tissue, 2 major sources of
  sRBP4, are likely not involved in this process
• Evidence for a myokine role of RBP4
• ? If RBP4 is a myokine, what would be its
  physiological role during exercise?

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Conclusion I

• Acute exercise-induced increases in sRBP4
  concentration are likely a result of increased
  skeletal muscle gene expression and RBP4
  secretion
• Liver and adipose tissue, 2 major sources of
  sRBP4, are likely not involved in this process
• Evidence for a myokine role of RBP4
• ? If RBP4 is a myokine, what would be its
  physiological role during exercise?

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What are the effects of RBP4 on exercise capacity?
First, some background
fvb mice H4IIe H4IIe

• Levels of the gluconeogenic enzyme hepatic PEPCK
  are regulated, either directly or indirectly, by
  (circulating?) RBP4.
• Implications on hepatic glucose production in
  vivo?
• functional connection to acute exercise?

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Hypothesis

• Due to the involvement of RBP4 in regulating
  hepatic glucose output, RBP4 deficient animals
  have reduced exercise capacity, and elevated
  post-exercise liver glycogen levels.

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Descriptive data RBP4 KO/WT mice
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Exercise graded exhaustive treadmill protocol
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Sedentary and exercise lactate levels
Why?
Decreased gluconeogenesis?
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Liver glycogen levels
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Conclusion II

• RBP4 KO mice have reduced exercise capacity
  compared to WT controls
• Some evidence that BG levels during exercise will
  decrease at an accelerated rate in KO animals
• Despite no apparent difference in sedentary
  glycogen, post-exercise glycogen levels are
  approximately 3-fold greater in KO compared to WT
  animals
• Liver glycogen metabolism during acute exercise
  may be impaired in RBP4 KO animals
• Post-exercise blood lactate levels are increased
  in RBP4 KO vs. WT animals ? impaired
  gluconeogenesis?