title: Thyroid Hormone Signaling in Male Mouse Skeletal Muscle Is Largely Independent of D2 in Myocytes.
abstract: The type 2 deiodinase (D2) activates the prohormone T4 to T3. D2 is expressed in skeletal muscle (SKM), and its global inactivation (GLOB-D2KO mice) reportedly leads to skeletal muscle hypothyroidism and impaired differentiation. Here floxed Dio2 mice were crossed with mice expressing Cre-recombinase under the myosin light chain 1f (cre-MLC) to disrupt D2 expression in the late developmental stages of skeletal myocytes (SKM-D2KO). This led to a loss of approximately 50% in D2 activity in neonatal and adult SKM-D2KO skeletal muscle and about 75% in isolated SKM-D2KO myocytes. To test the impact of Dio2 disruption, we measured soleus T3 content and found it to be normal. We also looked at the expression of T3-responsive genes in skeletal muscle, ie, myosin heavy chain I, α-actin, myosin light chain, tropomyosin, and serca 1 and 2, which was preserved in neonatal SKM-D2KO hindlimb muscles, at a time that coincides with a peak of D2 activity in control animals. In adult soleus the baseline level of D2 activity was about 6-fold lower, and in the SKM-D2KO soleus, the expression of only one of five T3-responsive genes was reduced. Despite this, adult SKM-D2KO animals performed indistinguishably from controls on a treadmill test, running for approximately 16 minutes and reached a speed of about 23 m/min; muscle strength was about 0.3 mN/m·g body weight in SKM-D2KO and control ankle muscles. In conclusion, there are multiple sources of D2 in the mouse SKM, and its role is limited in postnatal skeletal muscle fibers.
authors.affiliation: Division of Endocrinology and Metabolism (J.P.W.d.C., T.L.F., G.W.F., A.C.B.), Rush University Medical Center, Chicago Illinois 60612; Division of Endocrinology, Diabetes, and Metabolism (J.P.W.d.C., D.L.I., C.M.A.F., L.J.L., M.B.R.), University of Miami Miller School of Medicine, Miami, Florida 33101-6960; Biophysics Institute and School of Physical Education and Sports (J.P.W.d.C., D.L.I., M.B.R.), Federal University of Rio de Janeiro, 21941-901 Rio de Janeiro, Brazil; Developmental Disorders Program (M.O.R.), Center for Biological and Health Sciences, Mackenzie Presbyterian University, 01302 Sao Paulo, Brazil; Department of Endocrine Neurobiology (B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083 Hungary; and Translational Medicine (G.W.F.), Federal University of Sao Paulo, 01302-907 Sao Paulo, Brazil.
authors.forename: Joao P
authors.initials: JP
authors.lastname: Werneck-de-Castro
authors.affiliation: Division of Endocrinology and Metabolism (J.P.W.d.C., T.L.F., G.W.F., A.C.B.), Rush University Medical Center, Chicago Illinois 60612; Division of Endocrinology, Diabetes, and Metabolism (J.P.W.d.C., D.L.I., C.M.A.F., L.J.L., M.B.R.), University of Miami Miller School of Medicine, Miami, Florida 33101-6960; Biophysics Institute and School of Physical Education and Sports (J.P.W.d.C., D.L.I., M.B.R.), Federal University of Rio de Janeiro, 21941-901 Rio de Janeiro, Brazil; Developmental Disorders Program (M.O.R.), Center for Biological and Health Sciences, Mackenzie Presbyterian University, 01302 Sao Paulo, Brazil; Department of Endocrine Neurobiology (B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083 Hungary; and Translational Medicine (G.W.F.), Federal University of Sao Paulo, 01302-907 Sao Paulo, Brazil.
authors.forename: Tatiana L
authors.initials: TL
authors.lastname: Fonseca
authors.affiliation: Division of Endocrinology and Metabolism (J.P.W.d.C., T.L.F., G.W.F., A.C.B.), Rush University Medical Center, Chicago Illinois 60612; Division of Endocrinology, Diabetes, and Metabolism (J.P.W.d.C., D.L.I., C.M.A.F., L.J.L., M.B.R.), University of Miami Miller School of Medicine, Miami, Florida 33101-6960; Biophysics Institute and School of Physical Education and Sports (J.P.W.d.C., D.L.I., M.B.R.), Federal University of Rio de Janeiro, 21941-901 Rio de Janeiro, Brazil; Developmental Disorders Program (M.O.R.), Center for Biological and Health Sciences, Mackenzie Presbyterian University, 01302 Sao Paulo, Brazil; Department of Endocrine Neurobiology (B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083 Hungary; and Translational Medicine (G.W.F.), Federal University of Sao Paulo, 01302-907 Sao Paulo, Brazil.
authors.forename: Daniele L
authors.initials: DL
authors.lastname: Ignacio
authors.affiliation: Division of Endocrinology and Metabolism (J.P.W.d.C., T.L.F., G.W.F., A.C.B.), Rush University Medical Center, Chicago Illinois 60612; Division of Endocrinology, Diabetes, and Metabolism (J.P.W.d.C., D.L.I., C.M.A.F., L.J.L., M.B.R.), University of Miami Miller School of Medicine, Miami, Florida 33101-6960; Biophysics Institute and School of Physical Education and Sports (J.P.W.d.C., D.L.I., M.B.R.), Federal University of Rio de Janeiro, 21941-901 Rio de Janeiro, Brazil; Developmental Disorders Program (M.O.R.), Center for Biological and Health Sciences, Mackenzie Presbyterian University, 01302 Sao Paulo, Brazil; Department of Endocrine Neurobiology (B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083 Hungary; and Translational Medicine (G.W.F.), Federal University of Sao Paulo, 01302-907 Sao Paulo, Brazil.
authors.forename: Gustavo W
authors.initials: GW
authors.lastname: Fernandes
authors.affiliation: Division of Endocrinology and Metabolism (J.P.W.d.C., T.L.F., G.W.F., A.C.B.), Rush University Medical Center, Chicago Illinois 60612; Division of Endocrinology, Diabetes, and Metabolism (J.P.W.d.C., D.L.I., C.M.A.F., L.J.L., M.B.R.), University of Miami Miller School of Medicine, Miami, Florida 33101-6960; Biophysics Institute and School of Physical Education and Sports (J.P.W.d.C., D.L.I., M.B.R.), Federal University of Rio de Janeiro, 21941-901 Rio de Janeiro, Brazil; Developmental Disorders Program (M.O.R.), Center for Biological and Health Sciences, Mackenzie Presbyterian University, 01302 Sao Paulo, Brazil; Department of Endocrine Neurobiology (B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083 Hungary; and Translational Medicine (G.W.F.), Federal University of Sao Paulo, 01302-907 Sao Paulo, Brazil.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Andrade-Feraud
authors.affiliation: Division of Endocrinology and Metabolism (J.P.W.d.C., T.L.F., G.W.F., A.C.B.), Rush University Medical Center, Chicago Illinois 60612; Division of Endocrinology, Diabetes, and Metabolism (J.P.W.d.C., D.L.I., C.M.A.F., L.J.L., M.B.R.), University of Miami Miller School of Medicine, Miami, Florida 33101-6960; Biophysics Institute and School of Physical Education and Sports (J.P.W.d.C., D.L.I., M.B.R.), Federal University of Rio de Janeiro, 21941-901 Rio de Janeiro, Brazil; Developmental Disorders Program (M.O.R.), Center for Biological and Health Sciences, Mackenzie Presbyterian University, 01302 Sao Paulo, Brazil; Department of Endocrine Neurobiology (B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083 Hungary; and Translational Medicine (G.W.F.), Federal University of Sao Paulo, 01302-907 Sao Paulo, Brazil.
authors.forename: Lattoya J
authors.initials: LJ
authors.lastname: Lartey
authors.affiliation: Division of Endocrinology and Metabolism (J.P.W.d.C., T.L.F., G.W.F., A.C.B.), Rush University Medical Center, Chicago Illinois 60612; Division of Endocrinology, Diabetes, and Metabolism (J.P.W.d.C., D.L.I., C.M.A.F., L.J.L., M.B.R.), University of Miami Miller School of Medicine, Miami, Florida 33101-6960; Biophysics Institute and School of Physical Education and Sports (J.P.W.d.C., D.L.I., M.B.R.), Federal University of Rio de Janeiro, 21941-901 Rio de Janeiro, Brazil; Developmental Disorders Program (M.O.R.), Center for Biological and Health Sciences, Mackenzie Presbyterian University, 01302 Sao Paulo, Brazil; Department of Endocrine Neurobiology (B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083 Hungary; and Translational Medicine (G.W.F.), Federal University of Sao Paulo, 01302-907 Sao Paulo, Brazil.
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Ribeiro
authors.affiliation: Division of Endocrinology and Metabolism (J.P.W.d.C., T.L.F., G.W.F., A.C.B.), Rush University Medical Center, Chicago Illinois 60612; Division of Endocrinology, Diabetes, and Metabolism (J.P.W.d.C., D.L.I., C.M.A.F., L.J.L., M.B.R.), University of Miami Miller School of Medicine, Miami, Florida 33101-6960; Biophysics Institute and School of Physical Education and Sports (J.P.W.d.C., D.L.I., M.B.R.), Federal University of Rio de Janeiro, 21941-901 Rio de Janeiro, Brazil; Developmental Disorders Program (M.O.R.), Center for Biological and Health Sciences, Mackenzie Presbyterian University, 01302 Sao Paulo, Brazil; Department of Endocrine Neurobiology (B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083 Hungary; and Translational Medicine (G.W.F.), Federal University of Sao Paulo, 01302-907 Sao Paulo, Brazil.
authors.forename: Miriam O
authors.initials: MO
authors.lastname: Ribeiro
authors.affiliation: Division of Endocrinology and Metabolism (J.P.W.d.C., T.L.F., G.W.F., A.C.B.), Rush University Medical Center, Chicago Illinois 60612; Division of Endocrinology, Diabetes, and Metabolism (J.P.W.d.C., D.L.I., C.M.A.F., L.J.L., M.B.R.), University of Miami Miller School of Medicine, Miami, Florida 33101-6960; Biophysics Institute and School of Physical Education and Sports (J.P.W.d.C., D.L.I., M.B.R.), Federal University of Rio de Janeiro, 21941-901 Rio de Janeiro, Brazil; Developmental Disorders Program (M.O.R.), Center for Biological and Health Sciences, Mackenzie Presbyterian University, 01302 Sao Paulo, Brazil; Department of Endocrine Neurobiology (B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083 Hungary; and Translational Medicine (G.W.F.), Federal University of Sao Paulo, 01302-907 Sao Paulo, Brazil.
authors.forename: Balazs
authors.initials: B
authors.lastname: Gereben
authors.affiliation: Division of Endocrinology and Metabolism (J.P.W.d.C., T.L.F., G.W.F., A.C.B.), Rush University Medical Center, Chicago Illinois 60612; Division of Endocrinology, Diabetes, and Metabolism (J.P.W.d.C., D.L.I., C.M.A.F., L.J.L., M.B.R.), University of Miami Miller School of Medicine, Miami, Florida 33101-6960; Biophysics Institute and School of Physical Education and Sports (J.P.W.d.C., D.L.I., M.B.R.), Federal University of Rio de Janeiro, 21941-901 Rio de Janeiro, Brazil; Developmental Disorders Program (M.O.R.), Center for Biological and Health Sciences, Mackenzie Presbyterian University, 01302 Sao Paulo, Brazil; Department of Endocrine Neurobiology (B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083 Hungary; and Translational Medicine (G.W.F.), Federal University of Sao Paulo, 01302-907 Sao Paulo, Brazil.
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Bianco
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D015870:Gene Expression; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D053580:Muscle Strength / Q000235:genetics / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D018995:Myosin Heavy Chains / Q000235:genetics; D010805:Physical Conditioning, Animal / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics; D015398:Signal Transduction; D013963:Thyroid Hormones / Q000378:metabolism*; D013974:Thyroxine / Q000378:metabolism; D013997:Time Factors; D014284:Triiodothyronine / Q000378:metabolism; D014335:Tropomyosin / Q000235:genetics; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D018995:Myosin Heavy Chains; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013963:Thyroid Hormones; D013974:Thyroxine; D014284:Triiodothyronine; D014335:Tropomyosin; D000097564:Iodothyronine Deiodinase Type II; C519276:myosin heavy chain-1, mouse