Robert S. Rogers

Lean Body Mass and Weight-Bearing Activity in the Prediction of Bone Mineral Density in Physically Active Men

Rector, RS, Rogers, R, Ruebel, M, Widzer, MO, and Hinton, PS. Lean body mass and weight-bearing activity in the prediction of bone mineral density in physically active men. J Strength Cond Res 23(2): 427-435, 2009-Weight-bearing endurance activity and resistance exercise are recommended to help preserve bone health during adulthood. However, the effects of resistance training relative to those of weight-bearing endurance activity often are confounded by body weight and composition. The purpose of this study was to determine the effects of long-term running, cycling, and resistance training on whole-body and regional bone mineral density (BMD), adjusting for body weight and composition. Cyclists (CYCLE; n = 19), runners (RUN; n = 10), and resistance trained men (RT; n = 13) ages 19-45 years participated in this cross-sectional study. Current and lifetime bone loading was calculated using ground-reaction force values of the reported physical activities. Whole-body and regional BMD and body composition were assessed using dual X-ray absorptiometry. Bone turnover markers and hormones were measured in fasting serum samples. The RT athletes had significantly greater body weight, lean body mass (LBM), and fat mass than CYCLE and RUN athletes; percent body fat did not differ among groups. Unadjusted BMD at all sites was significantly greater in the RT compared with CYCLE and RUN. After adjusting for LBM, RUN had significantly greater spine BMD than CYCLE. Subjects LBM was a significant predictor of BMD in RT and CYCLE but not in RUN, suggesting that high-impact activity may override the benefits of LBM on BMD. Current bone loading was positively associated with serum osteocalcin concentrations (r = 0.480, p = 0.002). In conclusion, the results of the present study demonstrate that long-term running and resistance training increase BMD compared with cycling. However, it seems that high-impact activities, such as running, have a greater positive effect on BMD than resistance training.

Acute response of plasma markers of bone turnover to a single bout of resistance training or plyometrics

The time course of changes in plasma bone turnover markers following an acute bout of resistance training (RT) or plyometrics (PLY) has not been well characterized. This study is the first to compare the acute response of bone formation and resorption markers to a single bout of RT or PLY. Using a partially randomized, cross-over study design, 12 recreationally active men, aged 43 ± 5 yr, each completed four exercise trials: RT (Fed/Fasted) and PLY (Fed/Fasted). In addition to the RT and PLY trials, 5 of the original 12 participants also completed a fasted, no-exercise control trial to examine time-of-day variation. For each trial, blood was drawn immediately before exercise (PRE), immediately following exercise, and 15 min, 30 min, 1 h, 2 h, and 24 h following PRE for determination of plasma bone-specific alkaline phosphatase (BAP), osteocalcin (OC), tartrate-resistant acid phosphatase 5b (TRAP5b), COOH-terminal telopeptide of type I collagen (CTX), testosterone, parathyroid hormone, and cortisol. A one-factor repeated-measures ANOVA was performed for each trial to detect changes in bone markers during the 2 h following RT or PLY. TRAP5b transiently decreased during the 2 h following all exercise trials (main effect for time, P < 0.05), but returned to PRE concentrations 2 h postexercise. BAP, CTX, and OC remained unchanged, except for reductions in BAP and CTX following PLY-Fasted and PLY-Fed, respectively. During the control trial, BAP decreased, while TRAP5b, CTX, and OC remained unchanged. In general, plasma hormone concentrations decreased during the 2 h following PLY or RT, and cumulative decreases in TRAP5b during the 2 h following exercise were positively correlated with cumulative decreases in parathyroid hormone. The results of the present study suggest that the timing of the measurement of bone turnover markers relative to the last exercise bout is important for detection of exercise-associated changes in bone turnover markers, as the markers returned to preexercise values within 2 h of RT or PLY.

Post-transcriptional Inhibition of Hsc70-4/HSPA8 Expression Leads to Synaptic Vesicle Cycling Defects in Multiple Models of ALS

Amyotrophic lateral sclerosis (ALS) is a synaptopathy accompanied by the presence of cytoplasmic aggregates containing TDP-43, an RNA-binding protein linked to ∼97% of ALS cases. Using a Drosophila model of ALS, we show that TDP-43 overexpression (OE) in motor neurons results in decreased expression of the Hsc70-4 chaperone at the neuromuscular junction (NMJ). Mechanistically, mutant TDP-43 sequesters hsc70-4 mRNA and impairs its translation. Expression of the Hsc70-4 ortholog, HSPA8, is also reduced in primary motor neurons and NMJs of mice expressing mutant TDP-43. Electrophysiology, imaging, and genetic interaction experiments reveal TDP-43-dependent defects in synaptic vesicle endocytosis. These deficits can be partially restored by OE of Hsc70-4, cysteine-string protein (Csp), or dynamin. This suggests that TDP-43 toxicity results in part from impaired activity of the synaptic CSP/Hsc70 chaperone complex impacting dynamin function. Finally, Hsc70-4/HSPA8 expression is also post-transcriptionally reduced in fly and human induced pluripotent stem cell (iPSC) C9orf72 models, suggesting a common disease pathomechanism.

The role of laminins in the organization and function of neuromuscular junctions

The synapse between motor neurons and skeletal muscle is known as the neuromuscular junction (NMJ). Proper alignment of presynaptic and post-synaptic structures of motor neurons and muscle fibers, respectively, is essential for efficient motor control of skeletal muscles. The synaptic cleft between these two cells is filled with basal lamina. Laminins are heterotrimer extracellular matrix molecules that are key members of the basal lamina. Laminin α4, α5, and β2 chains specifically localize to NMJs, and these laminin isoforms play a critical role in maintenance of NMJs and organization of synaptic vesicle release sites known as active zones. These individual laminin chains exert their role in organizing NMJs by binding to their receptors including integrins, dystroglycan, and voltage-gated calcium channels (VGCCs). Disruption of these laminins or the laminin-receptor interaction occurs in neuromuscular diseases including Pierson syndrome and Lambert-Eaton myasthenic syndrome (LEMS). Interventions to maintain proper level of laminins and their receptor interactions may be insightful in treating neuromuscular diseases and aging related degeneration of NMJs.

A high fat diet alters metabolic and bioenergetic function in the brain: A magnetic resonance spectroscopy study.

Diet-induced obesity and associated metabolic effects can lead to neurological dysfunction and increase the risk of developing Alzheimers disease (AD) and Parkinsons disease (PD). Despite these risks, the effects of a high-fat diet on the central nervous system are not well understood. To better understand the mechanisms underlying the effects of high fat consumption on brain regions affected by AD and PD, we used proton magnetic resonance spectroscopy ((1)H-MRS) to measure neurochemicals in the hippocampus and striatum of rats fed a high fat diet vs. normal low fat chow. We detected lower concentrations of total creatine (tCr) and a lower glutamate-to-glutamine ratio in the hippocampus of high fat rats. Additional effects observed in the hippocampus of high fat rats included higher N-acetylaspartylglutamic acid (NAAG), and lower myo-inositol (mIns) and serine (Ser) concentrations. Post-mortem tissue analyses revealed lower phosphorylated AMP-activated protein kinase (pAMPK) in the striatum but not in the hippocampus of high fat rats. Hippocampal pAMPK levels correlated significantly with tCr, aspartate (Asp), phosphoethanolamine (PE), and taurine (Tau), indicating beneficial effects of AMPK activation on brain metabolic and energetic function, membrane turnover, and edema. A negative correlation between pAMPK and glucose (Glc) indicates a detrimental effect of brain Glc on cellular energy response. Overall, these changes indicate alterations in neurotransmission and in metabolic and bioenergetic function in the hippocampus and in the striatum of rats fed a high fat diet.

Heat shock proteins: in vivo heat treatments reveal adipose tissue depot-specific effects

Heat treatments (HT) and the induction of heat shock proteins (HSPs) improve whole body and skeletal muscle insulin sensitivity while decreasing white adipose tissue (WAT) mass. However, HSPs in WAT have been understudied. The purpose of the present study was to examine patterns of HSP expression in WAT depots, and to examine the effects of a single in vivo HT on WAT metabolism. Male Wistar rats received HT (41°C, 20 min) or sham treatment (37°C), and 24 h later subcutaneous, epididymal, and retroperitoneal WAT depots (SCAT, eWAT, and rpWAT, respectively) were removed for ex vivo experiments and Western blotting. SCAT, eWAT, and rpWAT from a subset of rats were also cultured separately and received a single in vitro HT or sham treatment. HSP72 and HSP25 expression was greatest in more metabolically active WAT depots (i.e., eWAT and rpWAT) compared with the SCAT. Following HT, HSP72 increased in all depots with the greatest induction occurring in the SCAT. In addition, HSP25 increased in the rpWAT and eWAT, while HSP60 increased in the rpWAT only in vivo. Free fatty acid (FFA) release from WAT explants was increased following HT in the rpWAT only, and fatty acid reesterification was decreased in the rpWAT but increased in the SCAT following HT. HT increased insulin responsiveness in eWAT, but not in SCAT or rpWAT. Differences in HSP expression and induction patterns following HT further support the growing body of literature differentiating distinct WAT depots in health and disease.

Effects of discontinuing a high-fat diet on mitochondrial proteins and 6-hydroxydopamine-induced dopamine depletion in rats.

Diet-induced obesity can increase the risk for developing age-related neurodegenerative diseases including Parkinsons disease (PD). Increasing evidence suggests that mitochondrial and proteasomal mechanisms are involved in both insulin resistance and PD. The goal of this study was to determine whether diet intervention could influence mitochondrial or proteasomal protein expression and vulnerability to 6-Hydroxydopamine (6-OHDA)-induced nigrostriatal dopamine (DA) depletion in rats nigrostriatal system. After a 3 month high-fat diet regimen, we switched one group of rats to a low-fat diet for 3 months (HF-LF group), while the other half continued with the high-fat diet (HF group). A chow group was included as a control. Three weeks after unilateral 6-OHDA lesions, HF rats had higher fasting insulin levels and higher Homeostasis model assessment of insulin resistance (HOMA-IR), indicating insulin resistance. HOMA-IR was significantly lower in HF-LF rats than HF rats, indicating that insulin resistance was reversed by switching to a low-fat diet. Compared to the Chow group, the HF group exhibited significantly greater DA depletion in the substantia nigra but not in the striatum. DA depletion did not differ between the HF-LF and HF group. Proteins related to mitochondrial function (such as AMPK, PGC-1α), and to proteasomal function (such as TCF11/Nrf1) were influenced by diet intervention, or by 6-OHDA lesion. Our findings suggest that switching to a low-fat diet reverses the effects of a high-fat diet on systemic insulin resistance, and mitochondrial and proteasomal function in the striatum. Conversely, they suggest that the effects of the high-fat diet on nigrostriatal vulnerability to 6-OHDA-induced DA depletion persist.

Impaired Mitophagy Plays a Role in Denervation of Neuromuscular Junctions in ALS Mice

Motor neurons in amyotrophic lateral sclerosis (ALS) patients and animal models show degeneration from the nerve terminal, known as dying-back neuropathy. To investigate the mechanism underlying this neuropathy, we analyzed the neuromuscular junctions (NMJs) and motor neuron cell bodies in SOD1G93A mice using electron microscopy. NMJs of SOD1G93A mice exhibited significantly higher numbers of autophagosomes and degenerated mitochondria compared to wild-type controls. Mitophagosomes were identified in the NMJ presynaptic terminals of wild-type mice and SOD1G93A mice. However, the number of mitophagosomes did not increase significantly in SOD1G93A NMJs indicating a defect in mitophagy, the autophagic process to degrade mitochondria. Consistent with this, proteins essential for mitophagy, p62/SQSTM1, Bnip3, Pink1, and Parkin were down-regulated in motor neurons in SOD1G93A mice. Importantly, SQSTM1 is one of the genes mutated in familial ALS patients. We evaluated the effect of impaired mitophagy on motor neurons by analyzing the double knockout mice of Pink1 and Parkin, two genes responsible for sensing depolarized mitochondria and delivering degenerated mitochondria to mitophagosomes. The double knockout mice exhibited NMJ degeneration, including axon swelling and NMJ fragmentation at 4 months of age. These phenotypes were rarely observed in wild-type control mice of the same age. The protein level of ATP synthase β subunit increased in the NMJ presynaptic terminals, suggesting the accumulation of mitochondria at NMJs of the double knockout mice. Importantly, NMJ denervation was observed in the double knockout mice. These data suggest that the reduced mitophagy function in motor neurons of SOD1G93A mice is one of the mechanisms causing degeneration of ALS NMJs.

Deficiency in the Heat Stress Response Could Underlie Susceptibility to Metabolic Disease

Heat treatment (HT) effectively prevents insulin resistance and glucose intolerance in rats fed a high-fat diet (HFD). The positive metabolic actions of heat shock protein 72 (HSP72), which include increased oxidative capacity and enhanced mitochondrial function, underlie the protective effects of HT. The purpose of this study was to test the ability of HSP72 induction to mitigate the effects of consumption of a short-term 3-day HFD in rats selectively bred to be low-capacity runners (LCRs) and high-capacity runners (HCRs)—selective breeding that results in disparate differences in intrinsic aerobic capacity. HCR and LCR rats were fed a chow or HFD for 3 days and received a single in vivo HT (41°C, for 20 min) or sham treatment (ST). Blood, skeletal muscles, liver, and adipose tissues were harvested 24 h after HT/ST. HT decreased blood glucose levels, adipocyte size, and triglyceride accumulation in liver and muscle and restored insulin sensitivity in glycolytic muscles from LCR rats. As expected, HCR rats were protected from the HFD. Importantly, HSP72 induction was decreased in LCR rats after only 3 days of eating the HFD. Deficiency in the highly conserved stress response mediated by HSPs could underlie susceptibility to metabolic disease with low aerobic capacity.

Heat shock protein 72 regulates hepatic lipid accumulation

Induction of the chaperone heat shock protein 72 (HSP72) through heat treatment (HT), exercise, or overexpression improves glucose tolerance and mitochondrial function in skeletal muscle. Less is known about HSP72 function in the liver where lipid accumulation can result in insulin resistance and nonalcoholic fatty liver disease (NAFLD). The purpose of this study was 1) to determine whether weekly in vivo HT induces hepatic HSP72 and improves glucose tolerance in rats fed a high-fat diet (HFD) and 2) to determine the ability of HSP72 to protect against lipid accumulation and mitochondrial dysfunction in primary hepatocytes. Male Wistar rats were fed an HFD for 15 wk and were given weekly HT (41°C, 20 min) or sham treatments (37°C, 20 min) for the final 7 wk. Glucose tolerance and insulin sensitivity were assessed, along with HSP72 induction and triglyceride storage, in the skeletal muscle and liver. The effect of an acute loss of HSP72 in primary hepatocytes was examined via siRNA. Weekly in vivo HT improved glucose tolerance, elevated muscle and hepatic HSP72 protein content, and reduced muscle triglyceride storage. In primary hepatocytes, mitochondrial morphology was changed, and fatty acid oxidation was reduced in small interfering HSP72 (siHSP72)-treated hepatocytes. Lipid accumulation following palmitate treatment was increased in siHSP72-treated hepatocytes. These data suggest that HT may improve systemic metabolism via induction of hepatic HSP72. Additionally, acute loss of HSP72 in primary hepatocytes impacts mitochondrial health as well as fat oxidation and storage. These findings suggest therapies targeting HSP72 in the liver may prevent NAFLD.