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En rine properties of skeletal muscle people courses umass edu

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					Endocrine properties of
   skeletal muscle
       Josef Brandauer

       Joslin Diabetes Center
josef.brandauer@joslin.harvard.edu




                                     1
                 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?



                                                    2
              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)




                                               3
            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)


                                                           4
                    Hormones

Hormao: Gr., ‘to set in motion’

First use of „hormone‟: Description of secretin, Bayliss
and Starling, 1902




                                                      5
          “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



                                                              6
            “Novel” endocrine glands

Heart: ANP, BNP: blood pressure regulation


Adipose tissue: leptin, adiponectin, etc.: satiety, insulin sensitivity,
etc.


Skeletal muscle: Interleukin-6, others?




                                                                    7
 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)?




                                             8
  Interleukin-6 (IL-6)




Febbraio, 2002




                         9
     Interleukin-6 (IL-6)




Steensberg, 2000



                            10
     Interleukin-6 (IL-6)




Febbraio, 2002


                            11
IL-6 before after hindlimb contraction




                                         12
        Retinol-binding protein 4 (RBP4)
Adipose-tissue G4KO animals are IR in vivo – in vitro glucose
transport is not affected




                                                                13
                               (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

                                                                    14
      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?




                                                     15
Acute exercise increases RBP4 in SD rats

          1.5
                            p = 0.03


          1.0
          AU


          0.5


                 10     5        11    11     6
          0.0
                Sed.    15        30   60     60'
                                             post
                                             Ex.


      AU, arbitrary units; Sed, sedentary, Exer., exercise;
      60 post, 60 min after exercise.
      (N = indicated in bars).

                                                              16
Where does the exercise-induced increase in sRBP4
                   originate?


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




                                               17
Acute exercise does not transiently induce
RBP4 mRNA in liver…



                   Liver m RNA corrected for Cyclophilin


     140.0

     120.0

     100.0

      80.0
     AU
      60.0

      40.0

      20.0

       0.0
              1
             sed               2
                             30 m in           603m in     1 hr 4post ex




                                                                           18
… or visceral fat



                      Visceral fat m RNA corrected for Cyclophilin


        180.0
        160.0

        140.0
        120.0
        100.0
      AU
         80.0
         60.0
         40.0

         20.0
          0.0
                  1
                sed                   30
                                      2 m in             3 60 m in   4 1 hr




                                                                              19
     … but …

    … acute exercise                       400
transiently increases                      350
                                                       0.014

      RBP4 mRNA in                         300




                        RBP4/Cyclophilin
      gastrocnemius


                          mRNA (RU)
                                           250
               muscle                      200

                                           150

                                           100
                                           50

                                            0
                                                 Sed   30' Exc   60' Exc   60' post Exc




    Additionally, muscle-specific hRBP4
 transgenic animals show an interesting
                         sRBP4 pattern:
                                                                                  20
     Soooo…..




… is RBP4 a “myokine”?




                         21
What does an individual muscle fiber show?




                                             22
 Retinol-binding protein 4 (RBP4)

non-contracted    contracted




                                    23
                     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?
                                                            24
                     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?
                                                            25
   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?                                        26
                   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.




                                                   27
Descriptive data – RBP4 KO/WT mice


                  Body weight (g)

          45
          40
          35
          30
          25
      g
          20
          15
          10
          5     39.3                38.9
          0
                 WT                 KO




                                           28
 Exercise – graded exhaustive treadmill protocol




               Exercise tim e (m in)                       Exercise expenditure (Joules)


       36:00                                         350
                                        *            300
       28:48
                                                     250                             *
       21:36                                         200
m in                                             J
       14:24                                         150

                                                     100
       07:12
                0:31:12                0:23:56       50
                                                                262                   189
       00:00                                          0
                 WT                     KO                        WT                KO




                                                                                            29
 Sedentary and exercise lactate levels
            Blood lactate levels in sed. and exercised                   Serum lactate levels in sedentary and
                    RBP4 KO and WT animals                               exercised RBP4 KO and WT animals
                                                                    20                                        *#
       25                                                                 WT
                                                                          KO
       20                                                           15




                                                             mmol
mmol




       15
                                                                    10                             0.08
       10
       5                                                            5
       0
                                                                    0
                  Sed WT      Ex. WT     Sed KO     Ex. KO                     Sed                        Ex.




       Why?                    Decreased gluconeogenesis?




                                                                                                                   30
                                     Liver glycogen levels



            Liver glycogen levels in sedentary RBP4 KO         Post-exercise liver glycogen (nmol/mg)
                              animals
          250                                            120
                                                                                 0.001
                   WT       KO
                                                         100
          200
nmol/mg




                                                         80
          150
                                                         60
          100
                                                         40
                    *            *
          50
                                                         20
           0
                                                          0
                        fasted                 fed                      WT                     KO




                                                                                                        31
                       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?

                                                                  32

				
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posted:4/19/2011
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