Predictors of muscle hypertrophy responsiveness to electrically evoked resistance training after spinal cord injury.

The purpose of the study was to identify potential predictors of muscle hypertrophy responsiveness following neuromuscular electrical stimulation resistance training (NMES-RT) in persons with chronic spinal cord injury (SCI). Data for twenty individuals with motor complete SCI who completed twice weekly NMES-RT lasting 12-16 weeks as part of their participation in one of two separate clinical trials were pooled and retrospectively analyzed. Magnetic resonance imaging (MRI) was used to measure muscle cross-sectional area (CSA) of the whole thigh and knee extensor muscle before and after NMES-RT. Muscle biopsies and fasting biomarkers were also measured. Following the completion of the respective NMES-RT trials, participants were classified into either high-responders (n = 8; muscle CSA > 20%) or low-responders (n = 12; muscle CSA < 20%) based on whole thigh muscle CSA hypertrophy. Whole thigh muscle and knee extensors CSAs were significantly greater (P < 0.0001) in high-responders (29 ± 7% and 47 ± 15%, respectively) compared to low-responders (12 ± 3% and 19 ± 6%, respectively). There were no differences in total caloric intake or macronutrient intake between groups. Extensor spasticity was lower in the high-responders compared to the low-responders as was the dosage of baclofen. Prior to the intervention, the high-responders had greater body mass compared to the low-responders with SCI (87.8 ± 13.7 vs. 70.4 ± 15.8 kg; P = 0.012), body mass index (BMI: 27.6 ± 2.7 vs. 22.9 ± 6.0 kg/m2; P = 0.04), as well as greater percentage in whole body and regional fat mass (P < 0.05). Furthermore, high-responders had a 69% greater increase (P = 0.086) in total Akt protein expression than low-responders. High-responders also exhibited reduced circulating IGF-1 with a concomitant increase in IGFBP-3. Exploratory analyses revealed upregulation of mRNAs for muscle hypertrophy markers [IRS-1, Akt, mTOR] and downregulation of protein degradation markers [myostatin, MurF-1, and PDK4] in the high-responders compared to low-responders. The findings indicate that body composition, spasticity, baclofen usage, and multiple signaling pathways (anabolic and catabolic) are involved in the differential muscle hypertrophy response to NMES-RT in persons with chronic SCI.

Neuromuscular electrical stimulation resistance training enhances oxygen uptake and ventilatory efficiency independent of mitochondrial complexes after spinal cord injury: a randomized clinical trial.

The purpose of the study was to determine whether neuromuscular electrical stimulation resistance training (NMES-RT)-evoked muscle hypertrophy is accompanied by increased V̇o2 peak, ventilatory efficiency, and mitochondrial respiration in individuals with chronic spinal cord injury (SCI). Thirty-three men and women with chronic, predominantly traumatic SCI were randomized to either NMES-RT (n = 20) or passive movement training (PMT; n = 13). Functional electrical stimulation-lower extremity cycling (FES-LEC) was used to test the leg V̇o2 peak, V̇E/V̇co2 ratio, and substrate utilization pre- and postintervention. Magnetic resonance imaging was used to measure muscle cross-sectional area (CSA). Finally, muscle biopsy was performed to measure mitochondrial complexes and respiration. The NMES-RT group showed a significant increase in postintervention V̇o2 peak compared with baseline (ΔV̇o2 = 14%, P < 0.01) with no changes in the PMT group (ΔV̇o2 = 1.6%, P = 0.47). Similarly, thigh (ΔCSAthigh = 19%) and knee extensor (ΔCSAknee = 30.4%, P < 0.01) CSAs increased following NMES-RT but not after PMT. The changes in thigh and knee extensor muscle CSAs were positively related with the change in V̇o2 peak. Neither NMES-RT nor PMT changed mitochondrial complex tissue levels; however, changes in peak V̇o2 were related to complex I. In conclusion, in persons with SCI, NMES-RT-induced skeletal muscle hypertrophy was accompanied by increased peak V̇o2 consumption which may partially be explained by enhanced activity of mitochondrial complex I.NEW & NOTEWORTHY Leg oxygen uptake (V̇o2) and ventilatory efficiency (V̇E/V̇co2 ratio) were measured during functional electrical stimulation cycling testing following 12-16 wk of either electrically evoked resistance training or passive movement training, and the respiration of mitochondrial complexes. Resistance training increased thigh muscle area and leg V̇o2 peak but decreased V̇E/V̇co2 ratio without changes in mitochondrial complex levels. Leg V̇o2 peak was associated with muscle hypertrophy and mitochondrial respiration of complex I following training.

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.

BACKGROUND: Persons with spinal cord injury (SCI) are at heightened risks of developing unfavorable cardiometabolic consequences due to physical inactivity. Functional electrical stimulation (FES) and surface neuromuscular electrical stimulation (NMES)-resistance training (RT) have emerged as effective rehabilitation methods that can exercise muscles below the level of injury and attenuate cardio-metabolic risk factors. Our aims are to determine the impact of 12 weeks of NMES + 12 weeks of FES-lower extremity cycling (LEC) compared to 12 weeks of passive movement + 12 weeks of FES-LEC on: (1) oxygen uptake (VO2), insulin sensitivity, and glucose disposal in adults with SCI; (2) skeletal muscle size, intramuscular fat (IMF), and visceral adipose tissue (VAT); and (3) protein expression of energy metabolism, protein molecules involved in insulin signaling, muscle hypertrophy, and oxygen uptake and electron transport chain (ETC) activities. METHODS/DESIGN: Forty-eight persons aged 18-65 years with chronic (> 1 year) SCI/D (AIS A-C) at the C5-L2 levels, equally sub-grouped by cervical or sub-cervical injury levels and time since injury, will be randomized into either the NMES + FES group or Passive + FES (control group). The NMES + FES group will undergo 12 weeks of evoked RT using twice-weekly NMES and ankle weights followed by twice-weekly progressive FES-LEC for an additional 12 weeks. The control group will undergo 12 weeks of passive movement followed by 12 weeks of progressive FES-LEC. Measurements will be performed at baseline (B; week 0), post-intervention 1 (P1; week 13), and post-intervention 2 (P2; week 25), and will include: VO2 measurements, insulin sensitivity, and glucose effectiveness using intravenous glucose tolerance test; magnetic resonance imaging to measure muscle, IMF, and VAT areas; muscle biopsy to measure protein expression and intracellular signaling; and mitochondrial ETC function. DISCUSSION: Training through NMES + RT may evoke muscle hypertrophy and positively impact oxygen uptake, insulin sensitivity, and glucose effectiveness. This may result in beneficial outcomes on metabolic activity, body composition profile, mitochondrial ETC, and intracellular signaling related to insulin action and muscle hypertrophy. In the future, NMES-RT may be added to FES-LEC to improve the workloads achieved in the rehabilitation of persons with SCI and further decrease muscle wasting and cardio-metabolic risks. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02660073 . Registered on 21 Jan 2016.

Abundance in proteins expressed after functional electrical stimulation cycling or arm cycling ergometry training in persons with chronic spinal cord injury.

STUDY DESIGN: Longitudinal design. OBJECTIVES: The study determined the effects of two forms of exercise training on the abundance of two proteins, (glucose transporter-4 [GLUT-4], adenosine monophosphate kinase [AMPK]) involved in glucose utilization and the transcriptional coactivator that regulates the genes involved in energy metabolism and mitochondrial biogenesis (peroxisome proliferator-activated receptor (PPAR) coactivator 1 alpha [PGC-1α]), in muscles in men with chronic motor-complete spinal cord injury (SCI). SETTINGS: Clinical trial at a Medical Center. METHODS: Nine men with chronic motor-complete SCI participated in functional electrical stimulation lower extremity cycling (FES-LEC; n = 4) or arm cycling ergometer (arm-cycling ergometer [ACE]; n = 5) 5 days/week for 16 weeks. Whole body composition was measured by dual energy X-ray absorptiometry. An intravenous glucose tolerance test was performed to measure glucose effectiveness (Sg) and insulin sensitivity (Si). Muscle biopsies of the right vastus lateralis (VL) and triceps muscles were collected one week prior to and post the exercise training intervention. RESULTS: Neither training intervention altered body composition or carbohydrate metabolism. GLUT-4 increased by 3.8 fold in the VL after FES training and increased 0.6 fold in the triceps after ACE training. PGC-1α increased by 2.3 fold in the VL after FES training and 3.8 fold in the triceps after ACE training. AMPK increased by 3.4 fold in the VL after FES training and in the triceps after ACE training. CONCLUSION: FES-LEC and ACE training were associated with greater protein expressions in the trained muscles by effectively influencing the abundance of GLUT-4, AMPK and PGC-1α. Thus, FES-LEC training of paralyzed muscle can modulate protein expression similar to that of trained and innervated muscle.

Electrical stimulation modulates Wnt signaling and regulates genes for the motor endplate and calcium binding in muscle of rats with spinal cord transection.

BACKGROUND: Spinal cord injury (SCI) results in muscle atrophy and a shift of slow oxidative to fast glycolytic fibers. Electrical stimulation (ES) at least partially restores muscle mass and fiber type distribution. The objective of this study was to was to characterize the early molecular adaptations that occur in rat soleus muscle after initiating isometric resistance exercise by ES for one hour per day for 1, 3 or 7 days when ES was begun 16 weeks after SCI. Additionally, changes in mRNA levels after ES were compared with those induced in soleus at the same time points after gastrocnemius tenotomy (GA). RESULTS: ES increased expression of Hey1 and Pitx2 suggesting increased Notch and Wnt signaling, respectively, but did not normalize RCAN1.4, a measure of calcineurin/NFAT signaling, or PGC-1ß mRNA levels. ES increased PGC-1α expression but not that of slow myofibrillar genes. Microarray analysis showed that after ES, genes coding for calcium binding proteins and nicotinic acetylcholine receptors were increased, and the expression of genes involved in blood vessel formation and morphogenesis was altered. Of the 165 genes altered by ES only 16 were also differentially expressed after GA, of which 12 were altered in the same direction by ES and GA. In contrast to ES, GA induced expression of genes related to oxidative phosphorylation. CONCLUSIONS: Notch and Wnt signaling may be involved in ES-induced increases in the mass of paralyzed muscle. Molecular adaptations of paralyzed soleus to resistance exercise are delayed or defective compared to normally innervated muscle.

Evolving concepts in neurogenic osteoporosis.

Convincing evidence has accumulated of regulation of bone by the central nervous system. The neural connection between brain and bone is mediated centrally by classic neurotransmitters and several neuropeptides, and peripherally by many of the same neurotransmitters and neuropeptides, albeit with actions opposite to their central effects. Pharmacologic blockade of ß2-adrenergic receptors or disruption of the gene encoding them increases bone mass, whereas increased activity of the sympathetic nervous system (SNS) contributes to bone loss. Brainstem serotonergic neurons regulate SNS activity and its modulation by leptin. Physiologic stimulation of osteoblastic nicotinic receptors results in proliferation and deposition of bone, whereas higher levels inhibit osteoblast function. Activation of sensory nerves has a centrally mediated action on bone, albeit poorly understood. The relative importance of, and interactions between autonomic, sensory, and peripheral nervous system actions on bone mass are also not clear in healthy individuals, and less so in pathologic states.

Nandrolone slows hindlimb bone loss in a rat model of bone loss due to denervation.

Nandrolone is an anabolic steroid that has been demonstrated to reduce the loss of bone and muscle from hindlimb unweighting and to slow muscle atrophy after nerve transection. To determine whether nandrolone has the ability to protect bone against loss due to disuse after denervation, male rats underwent sciatic nerve transaction, followed 28 days later by treatment with nandrolone or vehicle for 28 days. Bone mineral density (BMD) was determined 28 days later or 56 days after nerve transection. Denervation led to reductions in BMD of 7% and 12% for femur and tibia, respectively. Nandrolone preserved 80% and 60% of BMD in femur and tibia, respectively, demonstrating that nandrolone administration significantly reduced loss of BMD from denervation. This study offers a potential novel pharmacological strategy for use of nandrolone to reduce bone loss in severe disuse- and denervation-related bone loss, such as that which occurs after spinal cord injury.