Skeletal Muscle Hypertrophy and Cardio-Metabolic Benefits After Spinal Cord Injury

Hunter Holmes McGuire VA Medical Center, Virginia Commonwealth University, James J. Peters Veterans Affairs Medical Center

Spinal cord injury (SCI) is a devastating medical problem that affects thousands of civilian and military personnel in the United States. Spinal cord injuries (SCI) predispose individuals to impaired fitness, obesity, glucose intolerance and insulin resistance, placing them at greater risk for diabetes and coronary artery disease. These are devastating problems that occur frequently because of changes in body composition and reduced level of physical activity. Skeletal muscle wasting plays a central role in altered metabolism after SCI. Functional electrical stimulation (FES) is an effective rehabilitation tool that has been used to train the paralyzed skeletal muscles and which has shown some ability to ameliorate the deleterious effects of SCI on metabolism, particularly on insulin sensitivity. However, its ability to reverse skeletal muscle wasting is modest; most studies report limited gains in muscle mass and workload with highly variables outcomes from one study to another. This proposal was stimulated by the findings that a program of neuromuscular electrical stimulation resistance exercise prior to initiating functional electrical stimulation lower extremity cycling (FES-LEC) improves the gains in muscle mass and workload observed with FES. The specific objectives for the current proposal are to compare the impact of FES following evoking skeletal muscle hypertrophy of the lower extremity versus initiating FES cycling without introducing the hypertrophy effects on insulin sensitivity, control of blood sugar levels, oxygen uptake and amounts of muscle tissue and fat deposition. These studies could potentially have significant effects on thousands of people that will experience an SCI in the future as well as those living with SCI where prolonged paralysis is a major quality of life issue. There is a major need to investigate the mechanisms lead to maximize the benefits of FES applications and to understand cellular or molecular events that are associated with muscle hypertrophy and lead to promoting metabolic health after SCI. The designed study will provide a greater understanding regarding utilization of energy sources (like fats and sugars) in muscle

Primary Objectives Aim #1: To determine the impact of 12+12 weeks of neuromuscular electrical stimulation (NMES)+FES-LEC on oxygen uptake, insulin sensitivity and glucose uptake in adults with SCI compared to control + FES-LEC. Aim #2: To determine the impact of 12+12 weeks of NMES+FES-LEC on skeletal muscle size, infiltration of intramuscular fat, visceral adiposity as well as fatigue resistance compared to control+ FES-LEC. . Aim #3 : To determine the impact of 12+12 weeks of NMES+FES-LEC on determinants of energy metabolism, protein molecules involved in insulin signaling, muscle hypertrophy and oxygen uptake (IRS-1, adenosine monophosphate kinase (AMPK), glucose transporter (GLUT-4), insulin like growth factor (IGF-1), Akt, mammalian target of rapamycin (mTOR) and Peroxisome proliferator-activated receptor coactivator (PGC-1 alpha) and electron transport chain proteins compared to control + FES-LEC only. Subjects: Forty eight chronic (1 year or more post-injury) individuals with motor complete SCI will be recruited from the Hunter Holmes McGuire VA Spinal Cord Dysfunction registry and Virginia Commonwealth University over 4 years. Inclusion Criteria All participants will be between 18-65 years old, men/women, greater than one year post SCI, Body mass index (BMI) < 30 Kg/m2. Participants must have C5-L2 level of injury, traumatic motor complete or incomplete SCI [American Spinal Injury Impairment Scale Classification (AIS A, B or C)]. Exclusion Criteria: Participants with any of the following pre-existing medical conditions will be excluded (cardiovascular disease, uncontrolled type II diabetes mellitus, uncontrolled hypertension, and those on insulin, pressures sores stage 3 or greater), hematocrit above 50% or urinary tract infection or symptoms. Participants with osteoporosis (T-score equal or worse than -2.5 according to the World Health recommendation) will be excluded. Pregnant women and women who will be involved and become pregnant during the course of the study will be excluded as well. Study arms NMES+FES group (n =24; 2 days/week for 24 weeks); this group will undergo twice weekly of 12 weeks of surface NMES and ankle weights followed by 12 additional weeks of twice weekly of progressive FES-LEC using the RT300 bike. The total participation duration is 24 weeks +3 weeks for measurements. Control + FES group (n =24; 2 days/week for 24 weeks); this group will undergo twice weekly of 12 weeks of passive leg extension/flexion with no ankle weights followed by 12 additional weeks of twice weekly of progressive FES-LEC using the RT300 bike. The total participation duration is 24 weeks+3 weeks for measurements.

NMES+FES group (n=24; 2 days/week for 24 weeks); this group will undergo twice weekly of 12 weeks of surface NMES and ankle weights followed by 12 additional weeks of twice weekly of progressive FES-LEC using the RT300 bike. The total participation duration is 24 weeks +3 weeks for measurements.

Control+FES group (n=24; 2 days/week for 24 weeks); this group will undergo twice weekly of 12 weeks of passive leg extension/flexion with no ankle weights followed by 12 additional weeks of twice weekly of progressive FES-LEC using the RT300 bike. The total participation duration is 24 weeks+3 weeks for measurements.

12 weeks of electrically evoked resistance training followed by 12 weeks of functional electrical stimulation cycling.

Muscle Biopsy of the Vastus Lateralis Muscle. The Quantity of the Protein will be determined using Western Blot.

Muscle Biopsy of the Vastus Lateralis Muscle. Mitochondrial enzyme activities will be determined using biochemical assays.

Inclusion Criteria: All participants will be between 18-65 years old, men/women, Greater than one year post SCI, with body mass index (BMI) < 30 Kg/m2. . Participants must have traumatic motor complete or incomplete SCI C5-L2 level of injury, American Spinal Injury Impairment Scale Classification (AIS A, B or C). Exclusion Criteria: Participants with any of the following pre-existing medical conditions will be excluded (cardiovascular disease, uncontrolled type II DM, uncontrolled hypertension, and those on insulin, pressures sores stage 3 or greater), hematocrit above 50% or urinary tract infection or symptoms. Participants with osteoporosis (T-score equal or worse than -2.5 according to the World Health recommendation) will be excluded. Pregnant women and women who will be involved and become pregnant during the course of the study will be excluded as well.

Goldsmith JA, Lai RE, Garten RS, Chen Q, Lesnefsky EJ, Perera RA, Gorgey AS. Visceral Adiposity, Inflammation, and Testosterone Predict Skeletal Muscle Mitochondrial Mass and Activity in Chronic Spinal Cord Injury. Front Physiol. 2022 Feb 10;13:809845. doi: 10.3389/fphys.2022.809845. eCollection 2022.

Gorgey AS, Khalil RE, Davis JC, Carter W, Gill R, Rivers J, Khan R, Goetz LL, Castillo T, Lavis T, Sima AP, Lesnefsky EJ, Cardozo CC, Adler RA. Skeletal muscle hypertrophy and attenuation of cardio-metabolic risk factors (SHARC) using functional electrical stimulation-lower extremity cycling in persons with spinal cord injury: study protocol for a randomized clinical trial. Trials. 2019 Aug 23;20(1):526. doi: 10.1186/s13063-019-3560-8.