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.
Progressive resistance exercise training (PRT) is the most effective known intervention for combating aging skeletal muscle atrophy. However, the hypertrophic response to PRT is variable, and this ...may be due to muscle inflammation susceptibility. Metformin reduces inflammation, so we hypothesized that metformin would augment the muscle response to PRT in healthy women and men aged 65 and older. In a randomized, double‐blind trial, participants received 1,700 mg/day metformin (N = 46) or placebo (N = 48) throughout the study, and all subjects performed 14 weeks of supervised PRT. Although responses to PRT varied, placebo gained more lean body mass (p = .003) and thigh muscle mass (p < .001) than metformin. CT scan showed that increases in thigh muscle area (p = .005) and density (p = .020) were greater in placebo versus metformin. There was a trend for blunted strength gains in metformin that did not reach statistical significance. Analyses of vastus lateralis muscle biopsies showed that metformin did not affect fiber hypertrophy, or increases in satellite cell or macrophage abundance with PRT. However, placebo had decreased type I fiber percentage while metformin did not (p = .007). Metformin led to an increase in AMPK signaling, and a trend for blunted increases in mTORC1 signaling in response to PRT. These results underscore the benefits of PRT in older adults, but metformin negatively impacts the hypertrophic response to resistance training in healthy older individuals. ClinicalTrials.gov Identifier: NCT02308228.
Because metformin reduces inflammation, we hypothesized that it would augment the muscle response to progressive resistance exercise training (PRT) in healthy older participants. Following 14 weeks of PRT, metformin blunted gains in lean mass, thigh muscle mass, and thigh muscle density compared to placebo. Metformin did not affect increases in muscle macrophage abundance. However, metformin increased AMPK signaling, leading to a reduced mean increase in mTOR signaling.
Potential participants were identified by means of a daily hospital census, and patients were approached for enrollment irrespective of disease severity, except for those with unstable arrhythmias, ...congestive heart failure with a left ventricular ejection fraction of <25%, receiving mechanical ventilation, oxygen requirement of >5 L/min at rest, or other comorbidities that precluded participation in exercise, including orthopedic conditions and severe dementia. All participants received a comprehensive bundled care for readmission reduction during hospitalization and after discharge that was comprised of a uniform duration of 5 days of systemic steroids and antibiotics, disease management education, follow-up in the COPD clinic within 10 ± 2 days, smoking cessation counseling when applicable, home health or palliative care when suitable, and referrals to traditional PR (2). Baseline Characteristics of Patients in the Video Telehealth Pulmonary Rehabilitation and Unexposed Arms Telehealth PR (n = 80) Unexposed (n = 160) Age, yr 64.5 (10.1) 63.4 (11.8) Sex, F 49 (61.3%) 92 (57.5%) Race, African American 26 (32.5%) 57 (35.6%) Body mass index, kg/m2 29.0 (10.2) 28.2 (8.2) Current smoker 21 (26.3%) 60 (37.5%) FEV1% predicted* 45.4 (18.1) 48.6 (21.1) FEV1/FVC* 0.52 (0.15) 0.57 (0.15) Domiciliary oxygen use 43 (53.8%) 44 (27.5%) Coronary artery disease 16 (20.0%) 31 (19.4%) Atrial fibrillation 8 (10.0%) 13 (8.1%) Congestive heart failure 10 (12.5%) 24 (15.0%) Hypertension 55 (68.8%) 111 (69.4%) Diabetes mellitus 22 (27.5%) 46 (28.8%) Depression 16 (20.0%) 40 (25.0%) Anxiety 15 (18.8%) 32 (20.0%) Hospitalizations in prior 12 mo 0.9 (1.4) 0.9 (1.7) ER visits in prior 6 mo 1.0 (1.5) 0.7 (1.4) Length of stay, d† 4 (2) 4 (3) LACE index 10.7 (2.8) 10.6 (3.0) Definition of abbreviations: ER = emergency room; LACE = length of stay, acuity of admission, comorbidities, and ER visits in the previous 6 months; PR = pulmonary rehabilitation. A retrospective study of a comprehensive care plan comprised of smoking cessation and inhaler education; pulmonary consultation; comorbidity assessment; palliative care assessment; mucus clearance device and inhaler selection based on clinical assessment of patient dexterity, competence, and peak inspiratory flow; and close outpatient follow-up showed a 16% reduction in all-cause readmissions (4).
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.
Purpose
Cardiometabolic disease remains a leading cause of morbidity and mortality in developed nations. Consequently, identifying and understanding factors associated with underlying ...pathophysiological processes leading to chronic cardio metabolic conditions is critical. Metabolic health, arterial elasticity, and insulin sensitivity (SI) may impact disease risk, and may be determined in part by myofiber type. Therefore, the purpose of this study was to test the hypothesis that type I myofiber composition would be associated with high SI, greater arterial elasticity, lower blood pressure, and blood lipids; whereas, type IIx myofibers would be associated with lower SI, lower arterial elasticity, higher blood pressure, blood lipids.
Methods
Muscle biopsies were performed on the vastus lateralis in 16 subjects (BMI = 27.62 ± 4.71 kg/m
2
, age = 32.24 ± 6.37 years, 43% African American). The distribution of type I, IIa, and IIx myofibers was determined via immunohistochemistry performed on frozen cross-sections. Pearson correlation analyses were performed to assess associations between myofiber composition, SI, arterial elasticity, blood pressure, and blood lipid concentrations.
Results
The percentage of type I myofibers positively correlated with SI and negatively correlated with systolic blood pressure SBP, diastolic blood pressure, and mean arterial pressure (MAP); whereas, the percentage of type IIx myofibers were negatively correlated with SI and large artery elasticity, and positively correlated with LDL cholesterol, SBP, and MAP.
Conclusions
These data demonstrate a potential link between myofiber composition and cardiometabolic health outcomes in a cohort of premenopausal women. Future research is needed to determine the precise mechanisms in which myofiber composition impacts the pathophysiology of impaired glucose and lipid metabolism, as well as vascular dysfunction.
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 Parkinson's 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 Parkinson's disease (PD) and age-matched older adults.
INTRODUCTION/PURPOSEAerobic exercise training (AET) has been shown to improve mitochondrial bioenergetics and upregulate proteins related to lipid metabolism. However, it remains to be determined if ...these alterations associated with AET persist when measured in energy balance (EB) in the days after the last bout of training. The purpose of the study was to test the hypothesis that improvements in skeletal muscle mitochondrial function induced by AET observed in previous literature would persist when measured after restoring EB conditions 72 h removed from the last exercise bout.
METHODSParticipants were 14 premenopausal women (age = 31.2 ± 6.7 yr, BMI = 26.6 ± 5.1 kg·m). The AET program required three monitored training sessions per week for 8–16 wk. Skeletal muscle biopsies were obtained at baseline and after 8–16 wk of AET (≥72 h after the last exercise bout). All food was provided for 72 h before biopsies, and EB was managed 24 h before testing within ±100 kcal of measured energy requirements using a whole-room calorimeter. Mitochondrial oxidative capacity was quantified in permeabilized muscle fibers from the vastus lateralis.
RESULTSWe found that AET increased coupled respiration (154%) and uncoupled respiration (90%) rates using a fatty acid substrate (palmitoyl carnitine) (P < 0.05). However, when rates were normalized to complex IV activity (a marker of mitochondrial content), no significant differences were observed. In addition, there were no changes in proteins known to mediate mitochondrial biogenesis or lipid transport and metabolism after AET.
CONCLUSIONEight to 16 wk of AET improved mitochondrial capacity under fatty acid substrate when assessed in EB, which appears to be due to mitochondrial biogenesis.
We conducted, in persons with Parkinson's 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), Parkinson's Disease Quality of Life Scale (PDQ-39, -7.8pts); Unified Parkinson's 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.
ABSTRACT
Introduction
Myofiber type grouping is a histological hallmark of age‐related motor unit remodeling. Despite the accepted concept that denervation–reinnervation events lead to myofiber type ...grouping, the completeness of those conversions remains unknown.
Methods
Type I myofiber grouping was assessed in vastus lateralis biopsies from Young (26 ± 4 years; n = 27) and Older (66 ± 4 years; n = 91) adults. Grouped and ungrouped type I myofibers were evaluated for phenotypic differences.
Results
Higher type I grouping in Older versus Young was driven by more myofibers per group (i.e., larger group size) (P < 0.05). In Older only, grouped type I myofibers displayed larger cross‐sectional area, more myonuclei, lower capillary supply, and more sarco(endo)plasmic reticulum calcium ATPase I (SERCA I) expression (P < 0.05) than ungrouped type I myofibers.
Discussion
Grouped type I myofibers retain type II characteristics suggesting that conversion during denervation–reinnervation events is either progressive or incomplete. Muscle Nerve 57: E52–E59, 2018
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.
•Explosive power declines at an earlier age and to a greater degree than strength.•Magnitude and time course of whole muscle atrophy are similar in males and females.•Aging histopathological changes are more prominent in females.•Mechanistic studies into sex-specific myocellular aging are highly recommended.
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