Age-dependent regulation of skeletal muscle mitochondria by the thrombospondin-1 receptor CD47.
CD47, a receptor for thrombospondin-1, limits two important regulatory axes: nitric oxide-cGMP signaling and cAMP signaling, both of which can promote mitochondrial biogenesis. Electron microscopy revealed increased mitochondrial densities in skeletal muscle from both CD47 null and thrombospondin-1 null mice. We further assessed the mitochondria status of CD47-null vs WT mice. Quantitative RT-PCR of RNA extracted from tissues of 3 month old mice revealed dramatically elevated expression of mRNAs encoding mitochondrial proteins and PGC-1α in both fast and slow-twitch skeletal muscle from CD47-null mice, but modest to no elevation in other tissues. These observations were confirmed by Western blotting of mitochondrial proteins. Relative amounts of electron transport enzymes and ATP/O(2) ratios of isolated mitochondria were not different between mitochondria from CD47-null and WT cells. Young CD47-null mice displayed enhanced treadmill endurance relative to WTs and CD47-null gastrocnemius had undergone fiber type switching to a slow-twitch pattern of myoglobin and myosin heavy chain expression. In 12 month old mice, both skeletal muscle mitochondrial volume density and endurance had decreased to wild type levels. Expression of myosin heavy chain isoforms and myoglobin also reverted to a fast twitch pattern in gastrocnemius. Both CD47 and TSP1 null mice are leaner than WTs, use less oxygen and produce less heat than WT mice. CD47-null cells produce substantially less reactive oxygen species than WT cells. These data indicate that loss of signaling from the TSP1-CD47 system promotes accumulation of normally functioning mitochondria in a tissue-specific and age-dependent fashion leading to enhanced physical performance, lower reactive oxygen species production and more efficient metabolism.
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.
Elfaridah P
EP
Frazier
Jeff S
JS
Isenberg
Sruti
S
Shiva
Lei
L
Zhao
Paul
P
Schlesinger
Julie
J
Dimitry
Mones S
MS
Abu-Asab
Maria
M
Tsokos
David D
DD
Roberts
William A
WA
Frazier
D000375:Aging / Q000502:physiology*; D000818:Animals; D001823:Body Composition / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism*; D045303:Cytochromes b / Q000235:genetics; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism / Q000648:ultrastructure; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010807:Physical Endurance / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D019700:Thrombospondin 1 / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
D051928:CD47 Antigen; C497895:Cd47 protein, mouse; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D019700:Thrombospondin 1; D015534:Trans-Activators; D014157:Transcription Factors; C494763:Vdac1 protein, mouse; D013481:Superoxides; D045304:Cytochromes c; D045303:Cytochromes b; D050995:Voltage-Dependent Anion Channel 1; D018995:Myosin Heavy Chains
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