Resveratrol improves exercise performance and skeletal muscle oxidative capacity in heart failure.

We investigated whether treatment of mice with established pressure overload-induced heart failure (HF) with the naturally occurring polyphenol resveratrol could improve functional symptoms of clinical HF such as fatigue and exercise intolerance. C57Bl/6N mice were subjected to either sham or transverse aortic constriction surgery to induce HF. Three weeks postsurgery, a cohort of mice with established HF (%ejection fraction <45) was administered resveratrol (~450 mg·kg-1·day-1) or vehicle for 2 wk. Although the percent ejection fraction was similar between both groups of HF mice, those mice treated with resveratrol had increased total physical activity levels and exercise capacity. Resveratrol treatment was associated with altered gut microbiota composition, increased skeletal muscle insulin sensitivity, a switch toward greater whole body glucose utilization, and increased basal metabolic rates. Although muscle mass and strength were not different between groups, mice with HF had significant declines in basal and ADP-stimulated O2 consumption in isolated skeletal muscle fibers compared with sham mice, which was completely normalized by resveratrol treatment. Overall, resveratrol treatment of mice with established HF enhances exercise performance, which is associated with alterations in whole body and skeletal muscle energy metabolism. Thus, our preclinical data suggest that resveratrol supplementation may effectively improve fatigue and exercise intolerance in HF patients.NEW & NOTEWORTHY Resveratrol treatment of mice with heart failure leads to enhanced exercise performance that is associated with altered gut microbiota composition, increased whole body glucose utilization, and enhanced skeletal muscle metabolism and function. Together, these preclinical data suggest that resveratrol supplementation may effectively improve fatigue and exercise intolerance in heart failure via these mechanisms.

Brief electrical stimulation improves nerve regeneration after delayed repair in Sprague Dawley rats.

Functional recovery after peripheral nerve injury and surgical repair declines with time and distance because the injured neurons without target contacts (chronic axotomy) progressively lose their regenerative capacity and chronically denervated Schwann cells (SCs) atrophy and fail to support axon regeneration. Findings that brief low frequency electrical stimulation (ES) accelerates axon outgrowth and muscle reinnervation after immediate nerve surgery in rats and human patients suggest that ES might improve regeneration after delayed nerve repair. To test this hypothesis, common peroneal (CP) neurons were chronically axotomized and/or tibial (TIB) SCs and ankle extensor muscles were chronically denervated by transection and ligation in rats. The CP and TIB nerves were cross-sutured after three months and subjected to either sham or one hour 20Hz ES. Using retrograde tracing, we found that ES significantly increased the numbers of both motor and sensory neurons that regenerated their axons after a three month period of chronic CP axotomy and/or chronic TIB SC denervation. Muscle and motor unit forces recorded to determine the numbers of neurons that reinnervated gastrocnemius muscle demonstrated that ES significantly increased the numbers of motoneurons that reinnervated chronically denervated muscles. We conclude that electrical stimulation of chronically axotomized motor and sensory neurons is effective in accelerating axon outgrowth into chronically denervated nerve stumps and improving target reinnervation after delayed nerve repair. Possible mechanisms for the efficacy of ES in promoting axon regeneration and target reinnervation after delayed nerve repair include the upregulation of neurotrophic factors.

The basis for diminished functional recovery after delayed peripheral nerve repair.

The postsurgical period during which neurons remain without target connections (chronic axotomy) and distal nerve stumps and target muscles are denervated (chronic denervation) deleteriously affects functional recovery. An autologous nerve graft and cross-suture paradigm in Sprague Dawley rats was used to systematically and independently control time of motoneuron axotomy, denervation of distal nerve sheaths, and muscle denervation to determine relative contributions of each factor to recovery failure. Tibial (TIB) nerve was cross-sutured to common peroneal (CP) nerve via a contralateral 15 mm nerve autograft to reinnervate the tibialis anterior (TA) muscle immediately or after prolonging TIB axotomy, CP autograft denervation, or TA muscle denervation. Numbers of motoneurons that reinnervated TA muscle declined exponentially from 99 ± 15 to asymptotic mean (± SE) values of 35 ± 1, 41 ± 10, and 13 ± 5, respectively. Enlarged reinnervated motor units fully compensated for reduced motoneuron numbers after prolonged axotomy and autograft denervation, but the maximal threefold enlargement did not compensate for the severe loss of regenerating nerves through chronically denervated nerve stumps and for failure of reinnervated muscle fibers to recover from denervation atrophy. Muscle force, weight, and cross-sectional area declined. Our results demonstrate that chronic denervation of the distal stump plays a key role in reduced nerve regeneration, but the denervated muscle is also a contributing factor. That chronic Schwann cell denervation within the nerve autograft reduced regeneration less than after the denervation of both CP nerve stump and TA muscle, argues that chronic muscle denervation negatively impacts nerve regeneration.

Adaptive responses to creatine loading and exercise in fast-twitch rat skeletal muscle.

We investigated the effects of chronic creatine loading and voluntary running (Run) on muscle fiber types, proteins that regulate intracellular Ca2+, and the metabolic profile in rat plantaris muscle to ascertain the bases for our previous observations that creatine loading results in a higher proportion of myosin heavy chain (MHC) IIb, without corresponding changes in contractile properties. Forty Sprague-Dawley rats were assigned to one of four groups: creatine-fed sedentary, creatine-fed run-trained, control-fed sedentary, and control-fed run-trained animals. Proportion and cross-sectional area increased 10% and 15% in type IIb fibers and the proportion of type IIa fibers decreased 11% in the creatine-fed run-trained compared with the control-fed run-trained group (P < 0.03). No differences were observed in fast Ca2+-ATPase isoform SERCA1 content (P > 0.49). Creatine feeding alone induced a 41% increase (P < 0.03) in slow Ca2+-ATPase (SERCA2) content, which was further elevated by 33% with running (P < 0.02). Run training alone reduced parvalbumin content by 50% (P < 0.05). By comparison, parvalbumin content was dramatically decreased by 75% (P < 0.01) by creatine feeding alone but was not further reduced by run training. These adaptive changes indicate that elevating the capacity for high-energy phosphate shuttling, through creatine loading, alleviates the need for intracellular Ca2+ buffering by parvalbumin and increases the efficiency of Ca2+ uptake by SERCAs. Citrate synthase and 3-hydroxyacyl-CoA dehydrogenase activities were elevated by run training (P < 0.003) but not by run training + creatine feeding. This indicates that creatine loading during run training supports a faster muscle phenotype that is adequately supported by the existing glycolytic potential, without changes in the capacity for terminal substrate oxidation.

Effects of long-term creatine feeding and running on isometric functional measures and myosin heavy chain content of rat skeletal muscles.

The purpose of this study was to investigate whether creatine (Cr) supplementation during 12 weeks of phasic high-frequency voluntary wheel running would result in a faster myosin heavy chain (MHC) isoform profile in the rat mixed fast-twitch plantaris and alter its corresponding isometric contractile properties. The fast-twitch extensor digitorum longus and medial gastrocnemius and slow-twitch soleus were also studied. Forty weanling Sprague-Dawley male rats were assigned to one of four groups: creatine-sedentary (Cre-Sed); creatine-voluntary running (Cre-Run); control-sedentary (Con-Sed); control-voluntary running (Con-Run). Daily running distance was similar between Cre-Run and Con-Run. Average daily Cr ingestion was also similar being 2.4+/-0.17 and 3.0+/-0.14 g/kg in Cre-Sed and Cre-Run, respectively. Total creatine (TCr) content was elevated (P<0.03) in the plantaris of Cre-Run [211.4+/-16.9 mmol/kg dry weight (dw)], compared with Con-Run (175.1+/-5.69). In the plantaris, MHCIIb was 13% greater (P<0.00001) in Cre-Run compared with Con-Run, while MHCIId/x and MHCIIa were lower in Cre-Run by 7 and 6% (P<0.0002), respectively. No differences were observed in twitch force, time-to-peak tension, half-rise time or half-fall time. Greater tetanic force production (P<0.05) in Cre-Sed compared with Con-Sed corresponded to a 12% increase in MHCIId/x (P<0.0001) and a 12% decrease in MHCIIb (P<0.0006). The fatigue index of the plantaris at 10 s (FI(10s)) was reduced only after running (Cre-Run vs Con-Run), while in all other muscles the FI(10s) was lower only in the Cre-Sed group. In conclusion, Cr supplementation had differential effects on MHC isoform content and fatigability that depended on the level of contractile activity. Cr feeding combined with running exercise resulted in a faster MHC-based phenotype in the rat plantaris but the impact on associated isometric contractile properties was minimal.