Combination of hindlimb suspension and immobilization by casting exaggerates sarcopenia by stimulating autophagy but does not worsen osteopenia

Toni L. Speacht, Andrew R. Krause, Jennifer L. Steiner, Charles Lang, Henry J. Donahue

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Astronauts in space experience a unique environment that causes the concomitant loss of bone and muscle. However, the interaction between these tissues and how osteopenia and sarcopenia affect each other is unclear. We explored this relationship by exaggerating unloading-induced muscle loss using a unilateral casting model in conjunction with hindlimb suspension (HLS). Five-month-old, male C57Bl/6J mice subjected to HLS for 2 weeks displayed a significant decrease in gastrocnemius and quadriceps weight (−9–10%), with a two-fold greater decrease in muscle mass observed in the HLS + casted limb. However, muscle from casted limbs had a higher rate of protein synthesis (+16%), compared to HLS alone, with coordinated increases in S6K1 (+50%) and 4E-BP1 (+110%) phosphorylation. Increased protein content for surrogate markers of autophagy, including LC3-II (+75%), Atg7 (+10%), and Atg5-12 complex (+20%) was only detected in muscle from the casted limb. In proximal tibias, HLS resulted in significant decreases in bone volume fraction (−24% vs −8%), trabecular number (−6% vs +0.3%), trabecular thickness (−10% vs −2%), and trabecular spacing (+8.4% vs +2%) compared to ground controls. There was no further bone loss in casted limbs compared to HLS alone. In tibia midshafts, HLS resulted in decreased total area (−2% vs +1%) and increased bone mineral density (+1% vs −0.3%) compared to ground controls. Cortical bone from casted limbs showed an increase in cortical thickness (+9% vs +2%) and cortical area/total area (+1% vs −0.6%) compared to HLS alone. Our results suggest that casting exacerbates unloading-induced muscle loss via activation of autophagy. Casting did not exacerbate bone loss suggesting that the unloading-induced loss of muscle and bone can be temporally dissociated and the effect of reduced muscle activity plays a relatively minor role compared to reduced load bearing on trabecular bone structure.

Original languageEnglish (US)
Pages (from-to)29-37
Number of pages9
JournalBone
Volume110
DOIs
StatePublished - May 1 2018

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Sarcopenia
Hindlimb Suspension
Metabolic Bone Diseases
Autophagy
Muscles
Extremities
Bone and Bones
Tibia
Astronauts
Weight-Bearing
Bone Density
Proteins
Biomarkers
Phosphorylation
Weights and Measures

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

Cite this

Speacht, Toni L. ; Krause, Andrew R. ; Steiner, Jennifer L. ; Lang, Charles ; Donahue, Henry J. / Combination of hindlimb suspension and immobilization by casting exaggerates sarcopenia by stimulating autophagy but does not worsen osteopenia. In: Bone. 2018 ; Vol. 110. pp. 29-37.
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abstract = "Astronauts in space experience a unique environment that causes the concomitant loss of bone and muscle. However, the interaction between these tissues and how osteopenia and sarcopenia affect each other is unclear. We explored this relationship by exaggerating unloading-induced muscle loss using a unilateral casting model in conjunction with hindlimb suspension (HLS). Five-month-old, male C57Bl/6J mice subjected to HLS for 2 weeks displayed a significant decrease in gastrocnemius and quadriceps weight (−9–10{\%}), with a two-fold greater decrease in muscle mass observed in the HLS + casted limb. However, muscle from casted limbs had a higher rate of protein synthesis (+16{\%}), compared to HLS alone, with coordinated increases in S6K1 (+50{\%}) and 4E-BP1 (+110{\%}) phosphorylation. Increased protein content for surrogate markers of autophagy, including LC3-II (+75{\%}), Atg7 (+10{\%}), and Atg5-12 complex (+20{\%}) was only detected in muscle from the casted limb. In proximal tibias, HLS resulted in significant decreases in bone volume fraction (−24{\%} vs −8{\%}), trabecular number (−6{\%} vs +0.3{\%}), trabecular thickness (−10{\%} vs −2{\%}), and trabecular spacing (+8.4{\%} vs +2{\%}) compared to ground controls. There was no further bone loss in casted limbs compared to HLS alone. In tibia midshafts, HLS resulted in decreased total area (−2{\%} vs +1{\%}) and increased bone mineral density (+1{\%} vs −0.3{\%}) compared to ground controls. Cortical bone from casted limbs showed an increase in cortical thickness (+9{\%} vs +2{\%}) and cortical area/total area (+1{\%} vs −0.6{\%}) compared to HLS alone. Our results suggest that casting exacerbates unloading-induced muscle loss via activation of autophagy. Casting did not exacerbate bone loss suggesting that the unloading-induced loss of muscle and bone can be temporally dissociated and the effect of reduced muscle activity plays a relatively minor role compared to reduced load bearing on trabecular bone structure.",
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Combination of hindlimb suspension and immobilization by casting exaggerates sarcopenia by stimulating autophagy but does not worsen osteopenia. / Speacht, Toni L.; Krause, Andrew R.; Steiner, Jennifer L.; Lang, Charles; Donahue, Henry J.

In: Bone, Vol. 110, 01.05.2018, p. 29-37.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Combination of hindlimb suspension and immobilization by casting exaggerates sarcopenia by stimulating autophagy but does not worsen osteopenia

AU - Speacht, Toni L.

AU - Krause, Andrew R.

AU - Steiner, Jennifer L.

AU - Lang, Charles

AU - Donahue, Henry J.

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AB - Astronauts in space experience a unique environment that causes the concomitant loss of bone and muscle. However, the interaction between these tissues and how osteopenia and sarcopenia affect each other is unclear. We explored this relationship by exaggerating unloading-induced muscle loss using a unilateral casting model in conjunction with hindlimb suspension (HLS). Five-month-old, male C57Bl/6J mice subjected to HLS for 2 weeks displayed a significant decrease in gastrocnemius and quadriceps weight (−9–10%), with a two-fold greater decrease in muscle mass observed in the HLS + casted limb. However, muscle from casted limbs had a higher rate of protein synthesis (+16%), compared to HLS alone, with coordinated increases in S6K1 (+50%) and 4E-BP1 (+110%) phosphorylation. Increased protein content for surrogate markers of autophagy, including LC3-II (+75%), Atg7 (+10%), and Atg5-12 complex (+20%) was only detected in muscle from the casted limb. In proximal tibias, HLS resulted in significant decreases in bone volume fraction (−24% vs −8%), trabecular number (−6% vs +0.3%), trabecular thickness (−10% vs −2%), and trabecular spacing (+8.4% vs +2%) compared to ground controls. There was no further bone loss in casted limbs compared to HLS alone. In tibia midshafts, HLS resulted in decreased total area (−2% vs +1%) and increased bone mineral density (+1% vs −0.3%) compared to ground controls. Cortical bone from casted limbs showed an increase in cortical thickness (+9% vs +2%) and cortical area/total area (+1% vs −0.6%) compared to HLS alone. Our results suggest that casting exacerbates unloading-induced muscle loss via activation of autophagy. Casting did not exacerbate bone loss suggesting that the unloading-induced loss of muscle and bone can be temporally dissociated and the effect of reduced muscle activity plays a relatively minor role compared to reduced load bearing on trabecular bone structure.

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