S. Craig Tuggle

Heightened muscle inflammation susceptibility may impair regenerative capacity in aging humans

The regenerative response of skeletal muscle to mechanically induced damage is impaired with age. Previous work in our laboratory suggests this may result from higher proinflammatory signaling in aging muscle at rest and/or a greater inflammatory response to damage. We, therefore, assessed skeletal muscle proinflammatory signaling at rest and 24 h after unaccustomed, loaded knee extension contractions that induced modest muscle damage (72% increase in serum creatine kinase) in a cohort of 87 adults across three age groups (AGE40, AGE61, and AGE76). Vastus lateralis muscle gene expression and protein cell signaling of the IL-6 and TNF-α pathways were determined by quantitative PCR and immunoblot analysis. For in vitro studies, cell signaling and fusion capacities were compared among primary myoblasts from young (AGE28) and old (AGE64) donors treated with TNF-α. Muscle expression was higher (1.5- to 2.1-fold) in AGE76 and AGE61 relative to AGE40 for several genes involved in IL-6, TNF-α, and TNF-like weak inducer of apoptosis signaling. Indexes of activation for the proinflammatory transcription factors signal transducer and activator of transcription-3 and NF-κB were highest in AGE76. Resistance loading reduced gene expression of IL-6 receptor, muscle RING finger 1, and atrogin-1, and increased TNF-like weak inducer of apoptosis receptor expression. Donor myoblasts from AGE64 showed impaired differentiation and fusion in standard media and greater NF-κB activation in response to TNF-α treatment (compared with AGE28). We show for the first time that human aging is associated with muscle inflammation susceptibility (i.e., higher basal state of proinflammatory signaling) that is present in both tissue and isolated myogenic cells and likely contributes to the impaired regenerative capacity of skeletal muscle in the older population.

Novel, high-intensity exercise prescription improves muscle mass, mitochondrial function, and physical capacity in individuals with Parkinson's disease

We conducted, in persons with Parkinsons disease (PD), a thorough assessment of neuromotor function and performance in conjunction with phenotypic analyses of skeletal muscle tissue, and further tested the adaptability of PD muscle to high-intensity exercise training. Fifteen participants with PD (Hoehn and Yahr stage 2-3) completed 16 wk of high-intensity exercise training designed to simultaneously challenge strength, power, endurance, balance, and mobility function. Skeletal muscle adaptations (P < 0.05) to exercise training in PD included myofiber hypertrophy (type I: +14%, type II: +36%), shift to less fatigable myofiber type profile, and increased mitochondrial complex activity in both subsarcolemmal and intermyofibrillar fractions (I: +45-56%, IV: +39-54%). These adaptations were accompanied by a host of functional and clinical improvements (P < 0.05): total body strength (+30-56%); leg power (+42%); single leg balance (+34%); sit-to-stand motor unit activation requirement (-30%); 6-min walk (+43 m), Parkinsons Disease Quality of Life Scale (PDQ-39, -7.8pts); Unified Parkinsons Disease Rating Scale (UPDRS) total (-5.7 pts) and motor (-2.7 pts); and fatigue severity (-17%). Additionally, PD subjects in the pretraining state were compared with a group of matched, non-PD controls (CON; did not exercise). A combined assessment of muscle tissue phenotype and neuromuscular function revealed a higher distribution and larger cross-sectional area of type I myofibers and greater type II myofiber size heterogeneity in PD vs. CON (P < 0.05). In conclusion, persons with moderately advanced PD adapt to high-intensity exercise training with favorable changes in skeletal muscle at the cellular and subcellular levels that are associated with improvements in motor function, physical capacity, and fatigue perception.

Ribosome biogenesis may augment resistance training-induced myofiber hypertrophy and is required for myotube growth in vitro

Resistance exercise training (RT) is the most effective method for increasing skeletal muscle mass in older adults; however, the amount of RT-induced muscle growth is highly variable between individuals. Recent evidence from our laboratory and others suggests ribosome biogenesis may be an important factor regulating RT-induced hypertrophy, and we hypothesized that the extent of hypertrophy is at least partly regulated by the amount of RT-induced ribosome biogenesis. To examine this, 42 older adults underwent 4 wk of RT aimed at inducing hypertrophy of the knee extensors (e.g., 2 sets of squat, leg press, and knee extension, 10-12 repetition maximums, 3 days/wk), and vastus lateralis muscle biopsies were performed pre- and post-RT. Post hoc K-means cluster analysis revealed distinct differences in type II myofiber hypertrophy among subjects. The percent change in type II myofiber size in nonresponders (Non; n = 17) was -7%, moderate responders (Mod; n = 19) +22%, and extreme responders (Xtr; n = 6) +83%. Total muscle RNA increased only in Mod (+9%, P < 0.08) and Xtr (+26%, P < 0.01), and only Xtr increased rRNA content (+40%, P < 0.05) and myonuclei/type II fiber (+32%, P < 0.01). Additionally, Mod and Xtr had a greater increase in c-Myc protein levels compared with Non (e.g., approximately +350 and +250% vs. +50%, respectively, P < 0.05). In vitro studies showed that growth factor-induced human myotube hypertrophy is abolished when rRNA synthesis is knocked down using the Pol I-specific inhibitor CX-5461. Overall, these data implicate ribosome biogenesis as a key process regulating the extent of RT-induced myofiber hypertrophy in older adults.

Randomized, four-arm, dose-response clinical trial to optimize resistance exercise training for older adults with age-related muscle atrophy

Purpose: The myriad consequences of age‐related muscle atrophy include reduced muscular strength, power, and mobility; increased risk of falls, disability, and metabolic disease; and compromised immune function. At its root, aging muscle atrophy results from a loss of myofibers and atrophy of the remaining type II myofibers. The purpose of this trial (NCT02442479) was to titrate the dose of resistance training (RT) in older adults in an effort to maximize muscle regrowth and gains in muscle function. Methods: A randomized, four‐arm efficacy trial in which four, distinct exercise prescriptions varying in intensity, frequency, and contraction mode/rate were evaluated: (1) high‐resistance concentric‐eccentric training (H) 3 d/week (HHH); (2) H training 2 d/week (HH); (3) 3 d/week mixed model consisting of H training 2 d/week separated by 1 bout of low‐resistance, high‐velocity, concentric only (L) training (HLH); and (4) 2 d/week mixed model consisting of H training 1 d/week and L training 1 d/week (HL). Sixty‐four randomized subjects (65.5 ± 3.6 y) completed the trial. All participants completed the same 4 weeks of pre‐training consisting of 3 d/week followed by 30 weeks of randomized RT. Results: The HLH prescription maximized gains in thigh muscle mass (TMM, primary outcome) and total body lean mass. HLH also showed the greatest gains in knee extension maximum isometric strength, and reduced cardiorespiratory demand during steady‐state walking. HHH was the only prescription that led to increased muscle expression of pro‐inflammatory cytokine receptors and this was associated with a lesser gain in TMM and total body lean mass compared to HLH. The HL prescription induced minimal muscle regrowth and generally lesser gains in muscle performance vs. the other prescriptions. Major conclusions: The HLH prescription offers distinct advantages over the other doses, while the HL program is subpar. Although limited by a relatively small sample size, we conclude from this randomized dose‐response trial that older adults benefit greatly from 2 d/week high‐intensity RT, and may further benefit from inserting an additional weekly bout of low‐load, explosive RT. Trial registration: ClinicalTrials.gov NCT02442479 HighlightsHLH maximized gains in thigh muscle mass and total body lean mass.HLH induced the greatest gains in knee extension maximum isometric strength.HLH reduced cardiorespiratory demand during steady‐state walking.HHH led to increased muscle expression of pro‐inflammatory cytokine receptors.The HL prescription induced minimal muscle regrowth and lesser gains in performance.

Effects of aging and Parkinson's disease on motor unit remodeling: influence of resistance exercise training

Aging muscle atrophy is in part a neurodegenerative process revealed by denervation/reinnervation events leading to motor unit remodeling (i.e., myofiber type grouping). However, this process and its physiological relevance are poorly understood, as is the wide-ranging heterogeneity among aging humans. Here, we attempted to address 1) the relation between myofiber type grouping and molecular regulators of neuromuscular junction (NMJ) stability; 2) the impact of motor unit remodeling on recruitment during submaximal contractions; 3) the prevalence and impact of motor unit remodeling in Parkinsons disease (PD), an age-related neurodegenerative disease; and 4) the influence of resistance exercise training (RT) on regulators of motor unit remodeling. We compared type I myofiber grouping, molecular regulators of NMJ stability, and the relative motor unit activation (MUA) requirement during a submaximal sit-to-stand task among untrained but otherwise healthy young (YA; 26 yr, n = 27) and older (OA; 66 yr, n = 91) adults and OA with PD (PD; 67 yr, n = 19). We tested the effects of RT on these outcomes in OA and PD. PD displayed more motor unit remodeling, alterations in NMJ stability regulation, and a higher relative MUA requirement than OA, suggesting PD-specific effects. The molecular and physiological outcomes tracked with the severity of type I myofiber grouping. Together these findings suggest that age-related motor unit remodeling, manifested by type I myofiber grouping, 1) reduces MUA efficiency to meet submaximal contraction demand, 2) is associated with disruptions in NMJ stability, 3) is further impacted by PD, and 4) may be improved by RT in severe cases. NEW & NOTEWORTHY Because the physiological consequences of varying amounts of myofiber type grouping are unknown, the current study aims to characterize the molecular and physiological correlates of motor unit remodeling. Furthermore, because exercise training has demonstrated neuromuscular benefits in aged humans and improved innervation status and neuromuscular junction integrity in animals, we provide an exploratory analysis of the effects of high-intensity resistance training on markers of neuromuscular degeneration in both Parkinsons disease (PD) and age-matched older adults.

Human neuromuscular aging: Sex differences revealed at the myocellular level

&NA; Age‐related muscle loss (sarcopenia) is a major clinical problem affecting both men and women – accompanied by muscle weakness, dysfunction, disability, and impaired quality of life. Current definitions of sarcopenia do not fully encompass the age‐related changes in skeletal muscle. We therefore examined the influence of aging and sex on elements of skeletal muscle health using a thorough histopathological analysis of myocellular aging and assessments of neuromuscular performance. Two‐hundred and twenty‐one untrained males and females were separated into four age cohorts [mean age 25 y (n = 47), 37 y (n = 79), 61 y (n = 51), and 72 y (n = 44)]. Total (−12%), leg (−17%), and arm (−21%) lean mass were lower in both 61 y and 72 y than in 25 y or 37 y (P < 0.05). Knee extensor strength (−34%) and power (−43%) were lower (P < 0.05) in the older two groups, and explosive sit‐to‐stand power was lower by 37 y (P < 0.05). At the histological/myocellular level, type IIx atrophy was noted by 37 y and type IIa atrophy by 61 y (P < 0.05). These effects were driven by females, noted by substantial and progressive type IIa and IIx atrophy across age. Aged female muscle displayed greater within‐type myofiber size heterogeneity and marked type I myofiber grouping (˜5‐fold greater) compared to males. These findings suggest the predominant mechanisms leading to whole muscle atrophy differ between aging males and females: myofiber atrophy in females vs. myofiber loss in males. Future studies will be important to better understand the mechanisms underlying sex differences in myocellular aging and optimize exercise prescriptions and adjunctive treatments to mitigate or reverse age‐related changes.