Skeletal muscles of hibernating brown bears are unusually resistant to effects of denervation

Abstract

SUMMARYHibernating bears retain most of their skeletal muscle strength despite drastically reduced weight-bearing activity. Regular neural activation of muscles is a potential mechanism by which muscle atrophy could be limited. However, both mechanical loading and neural activity are usually necessary to maintain muscle size. An alternative mechanism is that the signaling pathways related to the regulation of muscle size could be altered so that neither mechanical nor neural inputs are needed for retaining strength. More specifically, we hypothesized that muscles in hibernating bears are resistant to a severe reduction in neural activation. To test this hypothesis, we unilaterally transected the common peroneal nerve, which innervates ankle flexor muscles, in hibernating and summer-active brown bears (Ursus arctos). In hibernating bears, the long digital extensor (LDE) and cranial tibial (CT) musculotendon masses on the denervated side decreased after 11weeks post-surgery by 18±11 and 25±10%, respectively, compared with those in the intact side. In contrast, decreases in musculotendon masses of summer-active bears after denervation were 61±4 and 58±5% in the LDE and CT, respectively, and significantly different from those of hibernating bears. The decrease due to denervation in summer-active bears was comparable to that occurring in other mammals. Whole-muscle cross-sectional areas (CSAs) measured from ultrasound images and myofiber CSAs measured from biopsies decreased similarly to musculotendon mass. Thus, hibernating bears alter skeletal muscle catabolic pathways regulated by neural activity, and exploration of these pathways may offer potential solutions for disuse atrophy of muscles.

Dynamic changes in global and gene specific DNA methylation during hibernation in adult thirteen-lined ground squirrels,Ictidomys tridecemlineatus

“…However, given the scale and nature of changes observed in muscle, we propose mechanisms of hypomethylation that act independently of methyltransferase function through passive (Kagiwada et al, 2013) or active demethylation (Kohli and Zhang, 2013). In passive demethylation, muscle-specific protection from atrophy and wasting during hibernation (Lin et al, 2012) suggests the possibility of myosatellite rejuvenation of the cell pool in the absence of DNMTs, leading to genomic hypomethylation. We speculate this molecular regulation of the myocyte cell line based on previous reports where this tissue was shown to have the highest variability in genomic methylation (Horvath, 2013), suggesting a dynamic role in cell fate during self-renewal (Motohashi and Asakura, 2012).…”

Skeletal muscle mass and composition during mammalian hibernation

“…Denervation of brown bear (Ursus arctos) cranial tibial and long digital extensor muscles in the summer results in profound atrophy over an 11 week period comparable to traditional denervation atrophy models (Lin et al, 2012). But when the same experiment is repeated during the winter, the atrophy response is greatly attenuated, suggesting that periodic muscle activity and loading may not be required for preservation of skeletal muscle during hibernation (Lin et al, 2012).…”

“…Denervation of brown bear (Ursus arctos) cranial tibial and long digital extensor muscles in the summer results in profound atrophy over an 11 week period comparable to traditional denervation atrophy models (Lin et al, 2012). But when the same experiment is repeated during the winter, the atrophy response is greatly attenuated, suggesting that periodic muscle activity and loading may not be required for preservation of skeletal muscle during hibernation (Lin et al, 2012). Similarly, when hibernating ground squirrels were sampled at multiple time points throughout the winter, fiber-type transitions had begun prior to initiation of torpor and were largely complete only a few weeks into the hibernating season (Nowell et al, 2011).…”

Activation of respiratory muscles does not occur during cold-submergence in bullfrogs,Lithobates catesbeianus

“…Broadly speaking, two plausible processes could maintain motor function throughout winter submergence. First, compensatory mechanisms at the cellular level could offset typical degradative processes caused by reduced activity in muscles and neurons as occurs in heterothermic hibernators and silent neural networks (Lee et al, 2008;Lin et al, 2012;Tessier and Storey, 2014;Turrigiano, 2012;Young et al, 2013). Second, the respiratory motor system may avoid the negative influence of inactivity by maintaining neuromotor activation during overwintering submergence.…”