The effects of resistance training on skeletal muscle senescent cell and denervation markers in older adults

Abstract

Emerging mechanisms associated with skeletal muscle aging include the increased presence of denervated myofibers and senescent cells. However, sparse research exists regarding how resistance training affects these outcomes. Thus, we sought to examine how eight weeks of unilateral leg extensor resistance training (2d/week) affected denervated myofibers, senescent stromal cells, and associated protein markers in untrained, middle-aged participants (MA, 55±8 years old, 17 females, 9 males). Vastus lateralis (VL) ultrasound images, biopsies, and strength assessments were obtained from the trained and untrained legs prior to (PRE) and following the intervention (POST). Type I/II/mixed fiber cross-sectional areas (fCSA), satellite cells (Pax7+), denervated myofibers (NCAM+), and senescent cells (p16+ or p21+) were assessed in 20 of these participants. In the trained leg of a subset of these participants, proteomics data was manually interrogated to examine proteins associated with muscle-nerve communication and senescence (n=18), and a targeted antibody-based array was used to examine senescence-associated secretory phenotype (SASP) protein expression (n=13). Leg extensor peak torque increased with training (p<0.001), and an interaction for muscle cross-sectional area approached significance (p=0.082) whereby hypertrophy favored the trained leg. While no significant interactions existed for I/II/mixed fCSAs, the percentage of NCAM+ type I/II/mixed myofibers, or senescent (p16+ or p21+) cells, a significant interaction (p=0.037) was evident for satellite cells whereby an increase occurred in the trained leg (p=0.020). Interestingly, while >90% satellite cells were not p16+ or p21+, most p16+ and p21+ cells were also Pax7+ (>90% on average) indicating that most senescent cells were satellite cells. Training altered 13/46 detected proteins related to muscle-nerve communication (all upregulated, p<0.05) and 10/19 proteins related to cellular senescence (9 upregulated, p<0.05). Of the SASP proteins, only 1/17 markers increased with training (IGFBP-3, p=0.031). In conclusion, while several proteins associated with muscle-nerve communication were upregulated in MA participants with training, NCAM+ myofibers were not altered. Moreover, resistance training in MA participants increased the abundance of senescence-related proteins in skeletal muscle, albeit this did not coincide with alterations in senescent cell numbers or SASP proteins. Finally, given that p16+ or p21+ were not affected with training, we speculate that the training-induced increase in satellite cells or the proliferation of an unidentified cell type may have accounted for the increases in senescence-related proteins, and that resistance training is not a driver of cellular senescence.