Blunted hypertrophic response in old mouse muscle is associated with a lower satellite cell density and is not alleviated by resveratrol

Abstract

Background: Sarcopenia contributes to the decreased quality of life in the older person.While resistance exercise is an effective measure to increase muscle mass and strength, the hypertrophic response may be blunted in old age.Objectives: To determine 1) whether hypertrophy in the m. plantaris of old mice was blunted compared to adult and 2) whether this was related to a reduced satellite cell (SC) density and 3) how resveratrol affects hypertrophy in old mice. Methods:In adult (7.5 months, n=11), old (23.5 months, n=10) and old-resveratrol-treated (n=10) male C57BL/6j mice, hypertrophy of the left m. plantaris was induced by denervation of its synergists. The contralateral leg served as control.Results: After six weeks, overload-induced myofiber hypertrophy and IIB-IIA shift in myofiber type composition were less pronounced in old than adult mice (P=0.03), irrespective of resveratrol treatment. Muscles from old mice had a lower SC density than adult muscles (P=0.002). Overload-induced SC proliferation (P<0.05) resulted in an increased SC density in old, but not adult muscles (P=0.02), while a decrease occurred after resveratrol supplementation (P=0.044). Id2 and myogenin protein expression levels were higher in old than adult muscles (P<0.05). Caspase-3 was expressed more in hypertrophied than control muscles and was reduced with resveratrol (P<0.05). Conclusion:The blunted hypertrophic response in old mice was associated with a lower SC density, but there was no evidence for a lower capacity for proliferation. Resveratrol did not rescue the hypertrophic response and even reduced, rather than increased, the number of SCs in hypertrophied muscles.

Blunted angiogenesis and hypertrophy are associated with increased fatigue resistance and unchanged aerobic capacity in old overloaded mouse muscle

“…Animals were given free access to water and chow (Ssniff® S8189-S095, the same as provided at the supplier). At the age of 7.5 or 23.5 months, the m. gastrocnemius and m. soleus of the left leg were denervated to overload the m. plantaris for 6 weeks (Ballak et al 2015; Degens and Alway 2003). The right leg served as internal control.…”

“…The daily intake of resveratrol was approximately 0.4 mg per gram body mass per day, based on a food intake of about 3 g per day. The food intake was most likely similar in old and old-res mice, since body mass did not change throughout the last 6 weeks prior to the terminal experiment in neither the old nor the old-res mice (Ballak et al 2015). …”

“…Frozen muscle tissue (~5–10 mg; 1:40, w / v ) was homogenized as described before (Ballak et al 2015). Homogenates were centrifuged at 10,000 g for 10 min at 4 °C.…”

“…This relationship is tightly regulated, as reflected by the similar time course of fiber hypertrophy and capillary proliferation in a rat model of compensatory hypertrophy (Egginton et al 2011; Plyley et al 1998). We therefore hypothesize that a lower muscle capillarization in old age, which would increase the diffusion distance for oxygen and thereby potentially limit muscle oxygenation (Degens et al 1993b; van der Laarse et al 2005), contributes to the impaired hypertrophic response observed in muscles from old rodents (Ballak et al 2015; Degens and Alway 2003) and humans (Kosek et al 2006; Welle et al 1996). …”

An apparent lack of effect of satellite cell depletion on hypertrophy could be due to methodological limitations. Response to ‘Methodological issues limit interpretation of negative effects of satellite cell depletion on adult muscle hypertrophy’

“…A very small increase or even reduction in crosssectional area (CSA) accompanied by an increase in the number of fibers has previously been reported in a few studies (Ferry et al, 2014;Joanne et al, 2012;Parsons et al, 2004), but to our knowledge not for observation periods as short as 2 weeks, and even most long-term studies report a robust hypertrophy (Ballak et al, 2016(Ballak et al, , 2015Dunn et al, 1999Dunn et al, , 2000Guerci et al, 2012;Ito et al, 2013;Johnson and Klueber, 1991;White et al, 2009). Although fiber splitting was not studied in either of the two papers, and is not a well-understood phenomenon, we agree that it is a reasonable speculation about the causes of the poor hypertrophy observed in the SC+OL+ muscles by (since we observed more robust hypertrophy, we think it less likely to be a significant issue in our own work).…”