Hindlimb muscle morphology and function in a new atrophy model combining spinal cord injury and cast immobilization.

University of Florida, Physical Therapy, Gainesville, Florida, United States
Journal of neurotrauma (Impact Factor: 3.97). 09/2012; DOI: 10.1089/neu.2012.2504
Source: PubMed

ABSTRACT Contusion spinal cord injury (SCI) animal models are used to study loss of muscle function and mass. However, parallels to the human condition typically have been confounded by spontaneous recovery observed within the first few post-injury weeks, partly due to free cage activity. We implemented a new rat model combining SCI with cast immobilization (IMM) to more closely reproduce the unloading conditions experienced by SCI patients. Magnetic resonance imaging was used to monitor hindlimb muscles cross-sectional area (CSA) after SCI, IMM alone, SCI combined with IMM (SCI+IMM) and in controls (CTR) over a period of 21 days. Soleus muscle tetanic force was measured in situ on day 21, and hindlimb muscles harvested for histology. IMM alone produced a decrease in triceps surae CSA to 63.9±4.9% of baseline values within 14 days. In SCI, CSA decreased to 75±10.5% after 7 days, and recovered to 77.9±10.7% by day 21. SCI+IMM showed the greatest amount of atrophy (56.9±9.9 % on day 21). In all groups, muscle mass and soleus tetanic force decreased in parallel, such that specific force was maintained. EDL and soleus fiber size decreased in all groups, particularly in SCI+IMM. We observed a significant degree of asymmetry in muscle CSA in SCI but not IMM. This effect increased between day 7 and 21 in SCI, but also in SCI+IMM, suggesting a minor dependence on muscle activity. SCI+IMM offers a clinically relevant model of SCI to investigate the mechanistic basis for skeletal muscle adaptations after SCI and develop therapeutic approaches.

1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Skeletal muscle undergoes continuous turnover to adapt to changes in its mechanical environment. Overload increases muscle mass, whereas underload decreases muscle mass. These changes are correlated with, and enabled by, structural alterations across the molecular, subcellular, cellular, tissue, and organ scales. Despite extensive research on muscle adaptation at the individual scales, the interaction of the underlying mechanisms across the scales remains poorly understood. Here, we present a thorough review and a broad classification of multiscale muscle adaptation in response to a variety of mechanical stimuli. From this classification, we suggest that a mathematical model for skeletal muscle adaptation should include the four major stimuli, overstretch, understretch, overload, and underload, and the five key players in skeletal muscle adaptation, myosin heavy chain isoform, serial sarcomere number, parallel sarcomere number, pennation angle, and extracellular matrix composition. Including this information in multiscale computational models of muscle will shape our understanding of the interacting mechanisms of skeletal muscle adaptation across the scales. Ultimately, this will allow us to rationalize the design of exercise and rehabilitation programs, and improve the long-term success of interventional treatment in musculoskeletal disease.
    Biomechanics and Modeling in Mechanobiology 09/2014; 14(2). DOI:10.1007/s10237-014-0607-3 · 3.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Skeletal muscle is a highly dynamic tissue that responds to endogenous and external stimuli, including alterations in mechanical loading and growth factors. In particular, the antigravity soleus muscle experiences significant muscle atrophy during disuse and extensive muscle damage upon reloading. Since insulin-like growth factor-1 (IGF-1) has been implicated as a central regulator of muscle repair and modulation of muscle size, we examined the effect of viral mediated overexpression of IGF-1 on the soleus muscle following hindlimb cast immobilization and upon reloading. Recombinant IGF-1 cDNA virus was injected into one of the posterior hindlimbs of the mice, while the contralateral limb was injected with saline (control). At 20 weeks of age, both hindlimbs were immobilized for two weeks to induce muscle atrophy in the soleus and ankle plantar flexor muscle group. Subsequently, the mice were allowed to reambulate and muscle damage and recovery was monitored over a period of 2 to 21 days. The primary finding of this study was that IGF-1 overexpression attenuated reloading-induced muscle damage in the soleus muscle, and accelerated muscle regeneration and force recovery. Muscle T2 assessed by MRI, a nonspecific marker of muscle damage, was significantly lower in IGF-1 injected, compared to contralateral soleus muscles at 2 and 5 days reambulation (P<0.05). The reduced prevalence of muscle damage in IGF-1 injected soleus muscles was confirmed on histology, with a lower fraction area of abnormal muscle tissue in IGF-I injected muscles at 2 days reambulation (33.2±3.3%vs 54.1±3.6%, P<0.05). Evidence of the effect of IGF-1 on muscle regeneration included timely increases in the number of central nuclei (21% at 5 days reambulation), paired-box transcription factor 7 (36% at 5 days), embryonic myosin (37% at 10 days), and elevated MyoD mRNA (7-fold at 2 days) in IGF-1 injected limbs (P<0.05). These findings demonstrate a potential role of IGF-1 in protecting unloaded skeletal muscles from damage and accelerating muscle repair and regeneration.
    Experimental physiology 01/2013; DOI:10.1113/expphysiol.2012.070722 · 2.87 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: Characterize bone loss in our newly developed severe contusion spinal cord injury (SCI) plus hindlimb immobilization (IMM) model and determine the influence of muscle contractility on skeletal integrity after SCI. Methods: Female Sprague-Dawley rats were randomized to: (a) intact controls, (b) severe contusion SCI euthanized at Day 7 (SCI-7) or (c) Day 21 (SCI-21), (d) 14 days IMM-alone, (e) SCI+IMM, or (f) SCI+IMM plus 14 days body weight supported treadmill exercise (SCI+IMM+TM). Results: SCI-7 and SCI-21 exhibited a >20% reduction in cancellous volumetric bone mineral density (vBMD) in the hindlimbs (p⋜0.01), characterized by reductions in cancellous bone volume (cBV/TV%), trabecular number (Tb.N), and trabecular thickness. IMM-alone induced no observable bone loss. SCI+IMM exacerbated cancellous vBMD deficits with values being >45% below Controls (p⋜0.01) resulting from reduced cBV/TV% and Tb.N. SCI+IMM also produced the greatest cortical bone loss with distal femoral cortical area and cortical thickness being 14-28% below Controls (p⋜0.01) and bone strength being 37% below Controls (p⋜0.01). SCI+IMM+TM partially alleviated bone deficits, but values remained below Controls. Conclusions: Residual and/or facilitated muscle contractility ameliorate bone decrements after severe SCI. Our novel SCI+IMM model represents a clinically-relevant means of assessing strategies to prevent SCI-induced skeletal deficits.
    Journal of musculoskeletal & neuronal interactions 09/2014; 14(3):255-266. · 2.40 Impact Factor