Interrogating adrenal dysfunction to prevent muscle wasting after acute spinal cord injury

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SUMMARY Traumatic spinal cord injury (SCI) is a devastating condition that affects ~18,000 Americans annually, resulting in death or a lifetime of severe disability. Early muscle wasting is an endemic consequence of SCI that contributes to mortality, impaired functional recovery and the development of secondary complications. Current interventions are not started until after considerable muscle wasting has already occurred during acute care and are minimally effective. To reduce mortality and maximize quality of life, mechanism-based interventions are needed to protect muscle and prevent wasting during the critical acute period ‘bridging’ between SCI and rehabilitation. Though denervation and inactivity of paralyzed muscles are common explanations for muscle wasting, they cannot explain the wasting of non-paralyzed muscles that occurs early after SCI. Interestingly, high thoracic level SCI concurrently exacerbates acute hypercortisolism and systemic muscle wasting, compared to low thoracic level SCI; Transient hypercortisolism during acute low thoracic SCI corresponds with transient non-paralyzed muscle wasting, whereas progressive hypercortisolism corresponds with enduring non-paralyzed muscle wasting during acute high thoracic SCI. SCI level-dependent hypercortisolism represents a systemic candidate signal exacerbating systemic muscle wasting since glucocorticoids potently induce muscle wasting. This research will investigate the cause of acute SCI level-dependent hypercortisolism and determine whether protecting muscle from glucocorticoids attenuates systemic muscle wasting during acute high thoracic level SCI. Based on pilot data, the investigators aim to determine whether SCI level-dependent acute hypercortisolism results from skewed sympathetic control over adrenal function. Hypothalamic-pituitary-adrenal (HPA)-axis hormones, HPA- axis function, and adrenal glucocorticoid synthesis during the acute phase of high and low thoracic SCI will be profiled. Then, it will be investigated whether shielding the adrenal glands from spinal sympathetic reflex activity by sympathetic denervation attenuates SCI level-dependent hypercortisolism. Subsequently, the investigators will determine whether preventing muscle exposure to glucocorticoids through pharmacological glucocorticoid receptor (GR) antagonism or knockout of muscle GR attenuates SCI level-dependent muscle wasting severity, as determined by measures of muscle mass, muscle function, muscle composition and gene/protein expression quantification of muscle wasting mediators. This research will be conducted by an MD/PhD candidate under the supervision of 2 leaders in the field of SCI research and in collaboration with 3 neuromuscular experts. The MD/PhD program is well established, and the institutional environment is exceptionally strong in SCI, myology and endocrine research. The training plan consists of opportunities to develop the foundational scientific knowledge, independence, technical expertise, communication skills, and creative and rigorous experimental design necessary to pursue an independent research career in the field of SCI.