Lee J. Winchester

Exercise mitigates the adverse effects of hyperhomocysteinemia on macrophages, MMP-9, skeletal muscle, and white adipocytes.

Regular exercise is a great medicine with its benefits encompassing everything from prevention of cardiovascular risk to alleviation of different muscular myopathies. Interestingly, elevated levels of homocysteine (Hcy), also known as hyperhomocysteinemia (HHcy), antagonizes beta-2 adrenergic receptors (β2AR), gamma amino butyric acid (GABA), and peroxisome proliferator-activated receptor-gamma (PPARγ) receptors. HHcy also stimulates an elevation of the M1/M2 macrophage ratio, resulting in a more inflammatory profile. In this review we discuss several potential targets altered by HHcy that result in myopathy and excessive fat accumulation. Several of these HHcy mediated changes can be countered by exercise and culminate into mitigation of HHcy induced myopathy and metabolic syndrome. We suggest that exercise directly impacts levels of Hcy, matrix metalloproteinase 9 (MMP-9), macrophages, and G-protein coupled receptors (GPCRs, especially Gs). While HHcy promotes the M1 macrophage phenotype, it appears that exercise may diminish the M1/M2 ratio, resulting in a less inflammatory phenotype. HHcy through its influence on GPCRs, specifically β₂AR, PPARγ and GABA receptors, promotes accumulation of white fat, whereas exercise enhances the browning of white fat and counters HHcy-mediated effects on GPCRs. Alleviation of HHcy-associated pathologies with exercise also includes reversal of excessive MMP-9 activation. Moreover, exercise, by reducing plasma Hcy levels, may prevent skeletal muscle myopathy, improve exercise capacity and rescue the obese phenotype. The purpose of this review is to summarize the pathological conditions surrounding HHcy and to clarify the importance of regular exercise as a method of disease prevention.

Hyperhomocysteinemia: a missing link to dysfunctional HDL via paraoxanase-1.

Paraoxanase-1 (PON1) is an HDL-associated enzyme that contributes to the antioxidant and antiatherosclerotic properties of HDL. Lack of PON1 results in dysfunctional HDL. HHcy is a risk factor for cardiovascular disorders, and instigates vascular dysfunction and ECM remodeling. Although studies have reported HHcy during atherosclerosis, the exact mechanism is unclear. Here, we hypothesize that dysfunctional HDL due to lack of PON1 contributes to endothelial impairment and atherogenesis through HHcy-induced ECM re-modeling. To verify this hypothesis, we used C57BL6/J and PON1 knockout mice (KO) and fed them an atherogenic diet. The expression of Akt, ADMA, and DDAH, as well as endothelial gap junction proteins such as Cx-37 and Cx-40 and eNOS was measured for vascular dysfunction and inflammation. We observed that cardiac function was decreased and plasma Hcy levels were increased in PON1 KO mice fed the atherogenic diet compared with the controls. Expression of Akt, eNOS, DDAH, Cx-37, and Cx-40 was decreased, and the expression of MMP-9 and ADMA was increased in PON1 KO mice fed an atherogenic diet compared with the controls. Our results suggest that HHcy plays an intricate role in dysfunctional HDL, owing to the lack of PON1. This contributes to vascular endothelial impairment and atherosclerosis through MMP-9-induced vascular remodeling.

Exercise mitigates the effects of hyperhomocysteinemia on adverse muscle remodeling

Hyperhomocysteinemia (HHcy) is known for causing inflammation and vascular remodeling, particularly through production of reactive oxygen species (ROS) and matrix metalloproteinase‐9 (MMP‐9) activation. Although its effect on the skeletal muscle is unclear, HHcy can cause skeletal muscle weakness and functional impairment by induction of inflammatory mediators and macrophage mediated injury. Exercise has been shown to reduce homocysteine levels and therefore, could serve as a promising intervention for HHcy. The purpose of this study was to investigate whether HHcy causes skeletal muscle fibrosis through induction of inflammation and determine whether exercise can mitigate these effects. C57BL/6J (WT) and CBS+/− (HHcy) mice were administered a 6 weeks treadmill exercise protocol. Hindlimb perfusion was measured via laser Doppler. Measurement of skeletal muscle protein expression was done by western blot. Levels of skeletal muscle MMP‐9 mRNA were determined by qPCR. Collagen deposition in the skeletal muscle was measured using Massons trichrome staining. In CBS+/− mice, HHcy manifested with decreased body weight and femoral artery lumen diameter, as well as a trend of lower hindlimb perfusion. These mice displayed increased wall to lumen ratio, mean arterial blood pressure, collagen deposition, and elevated myostatin protein expression. Exercise mitigated the effects above in CBS+/− mice. Skeletal muscle from CBS+/− mice had elevated markers of remodeling and hypoxia: iNOS, EMMPRIN, and MMP‐9. We conclude that HHcy causes skeletal muscle fibrosis possibly through induction of EMMPRIN/MMP‐9 and exercise is capable of mitigating the pathologies associated with HHcy.

Caffeine influences cadence at lower but not higher intensity RPE-regulated cycling

Caffeine blunts RPE estimations but effects on selected cycling cadence are unclear. PURPOSE This study examined influence of caffeine on cycling cadence with intensities prescribed at RPE 4 and 7 (OMNI Scale). METHODS College-aged (20.5±2.0y) male and female volunteers (n=15) (VO2 peak=40.3±4.0,) completed a maximal cycling test followed by trials where they adjusted cadence (CAD) (clamped resistances) to produce overall feelings equivalent to RPE 4 (RPE4) and RPE 7 (RPE7) (10min each) following caffeine (CAF) (6mg·kg-1·min-1) and placebo (PLA) (counterbalanced) ingestion. Participants were blinded to cadence during production trials. RESULTS Repeated measures ANOVA showed a significant main effect (trial) for CAD (CAF ~4rev·min-1 faster) for RPE4 but no significance for RPE7. Main effect for heart rate (HR) was not significant for RPE4 but significant for RPE7 (CAF ~4b·min-1 higher). Main effects showed mean VO2 significantly higher (~1.5-2ml·kg-1·min-1) for CAF for RPE4 and RPE7. Using a calculated least significant difference (5rev·min-1) positive responses were observed for five individuals (33%) for RPE4 and 3 individuals (20%) for RPE7. No negative (significantly slower cadences) responses were observed. RER in select trials suggested increased reliance on free fatty acid for CAF in responders. CONCLUSIONS Mean results show a mild effect of CAF on cadence selection during RPE production. However, assessing individual results more effectively clarifies ergogenic responses. Future research should identify factors responsible for diverse responses to caffeine during exercise.

Effect of a simulated tactical occupation task on physiological strain index, stress and inflammation

Background. This study aimed to evaluate the physiological strain index (PSI) along with specific immune system markers in response to a simulated firefighting occupation workload. Methods. Ten healthy male adults completed a 6-min simulated fire stair climb (SFSC) at 60 steps/min. The protocol consisted of four conditions, some including wearing a 34.04-kg vest to simulate personal protective equipment (PPE) and/or inclusion of a color-word interference test (CWIT) as a distracting mechanism. The PSI was evaluated by continuously monitoring the heart rate and core temperature. Salivary cortisol (CORT) was measured at baseline, mid SFSC and post SFSC. C-reactive protein (CRP) was evaluated at baseline and 1 h post SFSC. Results. Repeated-measures analysis of variance showed a significantly different PSI across conditions (p = 0.001). A significantly elevated PSI was exhibited during all 6 min of SFSC for both PPE and PPE + CWIT conditions. Neither CORT (p = 0.116) nor CRP (p = 0.700) was significantly different across conditions or from baseline. Conclusion. These findings suggest that firefighters are potentially at a substantial degree of physiological stress from exercise and the weight of gear alone. Further work should be conducted to further evaluate the usefulness of the PSI as a means to monitor firefighters during fire suppression.

Caffeine effects on velocity selection and physiological responses during RPE production

Caffeine (CAF) blunts estimated ratings of perceived exertion (RPE) but the effects on RPE production are unclear. This study examined effects of acute caffeine ingestion during treadmill exercise where participants exercised at prescribed RPE 4 and 7. Recreational runners (maximal oxygen consumption = 51.4 ± 9.8 mL·kg-1·min-1) (n = 16) completed a maximal treadmill test followed by trials where they selected treadmill velocity (VEL) (1% grade) to produce RPE 4 and RPE 7 (10 min each). RPE production trials followed CAF (6 mg·kg-1) or placebo (PLA) (counterbalanced) ingestion. Participants were blinded to treadmill VEL but the Omni RPE scale was in full view. Repeated-measures ANOVA showed a main effect (trial) for VEL (CAF ∼5 m·min-1 faster) for RPE 4 (p = 0.07) and RPE 7 (p = 0.03). Mean heart rate and oxygen consumption responses were consistently higher for CAF but failed to reach statistical significance. Individual responses to CAF were labeled positive using a criterion of 13.4 m·min-1 faster for CAF (vs. PLA). Ten of 32 trials (31%) were positive responses. In these, systematic increases were observed for heart rate (∼12 beats·min-1) and oxygen consumption (∼5.7 mL·kg-1·min-1). Blunted/stable respiratory exchange ratio values at higher VEL for positive responders suggest increased free fatty acid reliance during CAF. In conlusion, mean results show a mild effect of CAF during RPE production. However, individual responses more clearly indicate whether a true effect is possible. Trainers and individuals should consider individual responses to ensure effectively intensity regulation.