Exercise-mediated improvements in painful neuropathy associated with prediabetes in mice

Abstract

Recent research suggests that exercise can be effective in reducing pain in animals and humans with neuropathic pain. To investigate mechanisms in which exercise may improve hyperalgesia associated with prediabetes, C57Bl/6 mice were fed either standard chow or a high-fat diet for 12 weeks and were provided access to running wheels (exercised) or without access (sedentary). The high-fat diet induced a number of prediabetic symptoms, including increased weight, blood glucose, and insulin levels. Exercise reduced but did not restore these metabolic abnormalities to normal levels. In addition, mice fed a high-fat diet developed significant cutaneous and visceral hyperalgesia, similar to mice that develop neuropathy associated with diabetes. Finally, a high-fat diet significantly modulated neurotrophin protein expression in peripheral tissues and altered the composition of epidermal innervation. Over time, mice that exercised normalized with regards to their behavioral hypersensitivity, neurotrophin levels, and epidermal innervation. These results confirm that elevated hypersensitivity and associated neuropathic changes can be induced by a high-fat diet and exercise may alleviate these neuropathic symptoms. These findings suggest that exercise intervention could significantly improve aspects of neuropathy and pain associated with obesity and diabetes. Additionally, this work could potentially help clinicians determine those patients which will develop painful versus insensate neuropathy using intraepidermal nerve fiber quantification.

Supervised exercise improves cutaneous reinnervation capacity in metabolic syndrome patients

“…Nonetheless, this result suggests a salutary effect for exercise, and parallels rodent studies that find C57Bl/6 mice provided running wheel exercise avoid neuropathic pain associated with a high fat diet, even though they show no improvement in Metabolic Syndrome features. 33 …”

Comparing interval and continuous exercise training regimens on neurotrophic factors in rat brain

“…Also, it has been shown that long-term running at mod-102 erate intensity [5,23], contrary to short-term running [26], increased 103 GDNF concentration in the striatum and sciatic nerve. [27] and TNF-α production [28] The rats had free access to tap water and standard rat food (Javaneh [26].…”

Rats bred for low and high running capacity display alterations in peripheral tissues and nerves relevant to neuropathy and pain

“…Reductions in IENFD correlate with small fiber damage and sensory neuropathies (Lauria et al., 1999; Pittenger et al., 2004). Previous work by our group and others has displayed that IENFD is altered by changes in diet and exercise (Callaghan et al., 2016; Groover et al., 2013; Smith et al., 2006). Here, female LCR rats demonstrated a significant increase in the density of PGP‐9.5 + intraepidermal nerve fibers compared to HCR rats.…”

“…However, the overall percentage of TrkA fibers was similar between groups. Studies have established allodynia and reduced mechanical thresholds are associated with increased TrkA fibers (Cheng, Dauch, Hayes, Hong, & Feldman, 2009; Cheng, Dauch, Hayes, Yanik, & Feldman, 2012; Groover et al., 2013). This increase in IENF and increase in TrkA+ fiber density may predict that LCR rats display a greater response to evoked allodynia and are at risk for longer duration of heightened sensitivity.…”