Selective Pharmacological Inhibition of Myostatin with SRK-015P in a Contusion Model of SCI: Effects on Obesity, Muscle, and Cardioendocrine Pathology
Abstract
Objectives/Rationale for the Proposed Research: Spinal cord injury (SCI) normally causes significant muscle wasting below the injury level, which leads to weakness, infiltration of muscle with fat, and a significant decline in total body energy use. Diminished daily expenditure of energy increases whole body fat stores and promotes obesity and related diseases, such as diabetes. These so-called secondary complications of SCI impair health and function throughout the lifespan, making preservation of muscle after SCI a vital clinical priority. Studies have reported that muscle loss after SCI may be caused by overactivity of the myostatin molecule. In a recent pilot study, we tested mice with experimental SCI by blocking myostatin with an injectable antibody (SR-015), and found that muscle of treated animals with SCI was nearly the size of control animals without SCI, and also had much less fat. Whole body metabolism also remained near un-injured levels. Unlike control animals with SCI not receiving SR-015015, treated animals also had significantly higher scores when tested for skills of motor coordination. Thus, the primary objectives of the study are to test if injecting the antibody SR-015 against the myostatin molecule in mice with SCI: (1) prevents or reverses the loss of mass in muscles located below the injury, (2) prevents decline after SCI in the function of muscles as measured by tests of motor coordination, and (3) prevents fat infiltration of muscle below the lesion. We will also test body weight and fat mass, other tests of function, and the type of fibers and their size in muscles below the lesion. Our study design will also test whether SR-015 is more effective if given early after SCI or later, and whether hypothesized benefits are different in animals who eat normal food versus a high fat (obesity and diabetes-promoting) diet. Ultimate Applicability: Myostatin inhibitors are currently being tested in human clinical trials of other disability and aging groups as a treatment for muscle wasting and related health/functional decline. To date, no interventions used after SCI have successfully maintained large muscle masses below lesion level, even with time-consuming stakeholder efforts and sustained use of expensive equipment or therapy. While the current study is not a human clinical trial, the ultimate applicability will be to provide strong evidence that justifies trial testing, to inform how the investigators and the manufacturer of SR-015 should pursue first-in-SCI human studies, and to provide information needed by the U.S. Food and Drug Administration (FDA) to approve human testing. Thus, this study is required before human studies can be designed and receive government approval - our ultimate goal. Persons with SCI who the study may help, and how will it help them: Positive outcomes of the study will provide the first evidence for myostatin inhibition as a legitimate clinical treatment for muscle wasting and obesity-diabetes disease prevention after SCI. As the loss of muscle mass below lesion level causes undesirable changes in multiple body systems and also promotes secondary health complications and functional decline, we expect the proposed preclinical work will validate a unique, yet an untested method for sustaining and recovering muscle mass (health) and related function after SCI. Potential Clinical Applications, Benefits, and Risks: In addition to treatment of "complete motor injuries," the work has potential benefits for persons with partial sparing of muscle (i.e., incomplete SCI), and may make recovery of strength and function easier to maintain or recover. It may also preserve the size and function of denervated (i.e., flaccid) muscles in lower level injuries, which typically lose all contraction after injury and become permanently consolidated by connective tissue. Our study design also incorporates subgroups that test SRK-015 in both early and later stages of SCI, so that benefits
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810775
Entities
People
- Mark Nash
Organizations
- United States Army
- University of Miami