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C O M P L E T E T I T L E : Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double‐blind, placebo‐controlled, multicenter trial: The MASTERS trial.
F U L L T E X T S O U R C E : Aging Cell
Abstract
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.
1 INTRODUCTION
In elderly persons, muscle mass is highly correlated with limited mobility, disability, and mortality (Han, Bokshan, Marcaccio, DePasse, & Daniels, 2018). Resistance exercise training (RT) is the most effective therapy for sarcopenia and has been shown to increase muscle fiber size, muscle mass, and strength (Taaffe, Pruitt, Pyka, Guido, & Marcus, 1996). Accordingly, RT has also been shown to improve activities of daily living, overall health, and quality of life in elderly individuals (Hunter, McCarthy, & Bamman, 2004). However, hypertrophic and functional improvements following RT vary among individuals, with some people completely failing to experience muscle hypertrophy (Stec et al., 2017). Numerous conditions may contribute to the nonresponder phenotype in some older adults, including anabolic resistance (Fry & Rasmussen, 2011), chronic low‐grade inflammation (Dalle, Rossmeislova, & Koppo, 2017), and muscle‐specific inflammation (Merritt et al., 2013).
Metformin has been among the top 10 most widely prescribed drugs in the United States for nearly two decades (ClinCalc DrugStats Database, clincalc.com/DrugStats; Marshall, 2017). Metformin enhances insulin‐stimulated glucose uptake in rodents (Peixoto et al., 2017) and in muscle cell culture (Galuska, Nolte, Zierath, & Wallberg‐Henriksson, 1994), although in humans its main effect is to inhibit hepatic glucose output (Yu, Kruszynska, Mulford, & Olefsky, 1999). Metformin has also been shown to reduce inflammation in muscle (Amin, Hussein, Yassa, Hassan, & Rashed, 2018; Peixoto et al., 2017). At the tissue level, macrophages are important mediators of inflammatory signaling; metformin promotes polarization of pro‐inflammatory M1 macrophages to anti‐inflammatory M2 macrophages in murine adipose tissue (Amin et al., 2018) and bone marrow‐derived monocytes (Cameron et al., 2016). We recently showed that resident M2 muscle macrophages are associated with exercise‐mediated increases in skeletal muscle satellite cells and fiber size (Walton et al., 2019). In addition, we previously found that resting muscle tissue of many older adults is in a heightened, local state of inflammation susceptibility (Merritt et al., 2013). Based on these combined data, we hypothesized that metformin may improve the muscle response to RT by increasing the abundance of M2 macrophages, thereby reducing muscle inflammation.
In the absence of RT, metformin appears to delay lean mass loss in men with type 2 diabetes (Lee et al., 2011). However, when adults with prediabetes underwent concurrent aerobic and resistance training, metformin appeared to blunt exercise‐induced gains in lean mass (Malin, Gerber, Chipkin, & Braun, 2012). It is unknown whether metformin treatment can augment lean mass gains during RT in healthy older individuals. In The Metformin to Augment Strength Training Effective Response in Seniors (MASTERS) randomized trial, we determined whether the hypertrophic response to progressive RT (PRT) would be improved by the addition of metformin compared to placebo (Long et al., 2017).
2 RESULTS
2.1 Study participants and design
Baseline characteristics of study participants are given in Table 1. At the University of Alabama at Birmingham (UAB), 104 subjects were screened and 76 were randomized. At the University of Kentucky (UK), 41 subjects were screened and 33 were randomized. Of 109 randomized subjects, 15 participants discontinued the study (n = 6 due to adverse events), resulting in a final analytic sample of 94 (86%) who completed the study (n = 46 Metformin; n = 48 Placebo). Baseline characteristics and dropout rates were similar between treatment groups. The Consort diagram is shown in Appendix S1: Figuer 1. Among randomized subjects, 56% were female. Median age was 69.3 (interquartile range [IQR] 66.9–73.0), and mean BMI was 26.3 (SD 3.2). The participants tended to be high functioning, with a median Short Physical Performance Battery (SPPB) score of 11.0 (IQR 10–12). Similarly, questionnaire‐based indices suggested high function in our participants: Median Physical Activity Scale for the Elderly score was 158.7 (IQR 124.3–207.9); median 36‐Item Short Form Survey Instrument (SF‐36) Physical component norm‐based score was 54.8 (IQR 49.4–57.6); and median SF‐36 Mental component norm‐based score was 56.5 (IQR 53.8–59.2). The 109 randomized subjects included 105 Caucasians, three African Americans, and one Asian. (See table at source).
An overview of the study design is shown in Figure 1. Subjects were randomized to receive either placebo or metformin, which was titrated up to the target dose of 1,700 mg/day, consistent with doses that are prescribed for diabetes and prediabetes (Hess, Unger, Madea, Stratmann, & Tschoepe, 2018), for the duration of the trial. Following a 2‐week drug wash‐in period, and a 2‐week PRT familiarization and ramp‐up period, baseline strength testing was performed. All participants then continued to perform 12 more weeks of supervised, variable intensity, bilateral, upper, and lower body PRT. Participants received metformin or placebo for the entire duration of PRT and through post‐training assessments. Dual‐energy X‐ray absorptiometry (DXA) scans, mid‐thigh computed tomography (CT) scans, muscle biopsies, and oral glucose tolerance tests were performed at baseline and 3 days after the final exercise bout, to assess chronic effects of the intervention. While 60% of participants who completed the placebo arm were female, 48% of participants who completed the metformin arm were female. Although sex distribution was not significantly different between groups (χ2 (df = 1) = 1.50, p = .221), the sex distribution led to significant differences in baseline measures. To account for sex differences at baseline and following training, we compared percent changes in all measured outcome variables except for those that were already percent‐based (percent fat and percent fiber type frequency).
Figure 1
A schematic representation of the study design. CT, computed tomography; DXA, dual‐energy X‐ray absorptiometry; OGTT, oral glucose tolerance test; PRT, progressive resistance training.
Medication and exercise compliance data are given in Appendix S1. Adverse events were more likely to occur with metformin (χ2 (df = 1) = 9.82, p = .002) (Appendix S1: Table 1). Deviations from the study protocol included randomization of 13 obese subjects (BMI 30–33.9). Additionally, five subjects completed fewer than 37 exercise sessions prior to undergoing the final muscle biopsy. A summary and explanation of missing data are given in Appendix S1: Table 2.
Nearly all participants underwent some beneficial physiological adaptations in response to PRT. Appendix S2: Table 1 shows the effect of PRT for all measured outcomes in those who completed the trial. Appendix S2: Table 2 shows the effects of PRT within each treatment group.
2.2 Metformin inhibits PRT‐induced gains in total lean mass and thigh muscle mass; metformin trends toward inhibiting strength gains
Changes in body weight, diet, and glucose metabolism are shown in Appendix S3. PRT induced weight loss in most participants, with no effect of metformin. Dietary intake was not affected by PRT, with or without metformin (Appendix S3: Table 1). Although fasting glucose was decreased in placebo by −3.35% (SD 7.46) (p = .003), metformin had a mean nonsignificant decrease of −1.59% (SD 7.99) (p = .184); nonetheless, changes in fasting glucose did not differ between treatment groups (p = .272) (Appendix S2: Table 2; Appendix S3: Table 1). Insulin sensitivity was improved by PRT in both groups, with no significant difference between groups (Appendix S2: Table 2; Appendix S3: Table 1).
We used DXA to assess body composition at baseline and after PRT (Figure 2). PRT led to a reduction in percent fat, with no difference between groups; mean decrease in percent fat was −1.86 (SD 2.08) with placebo and −2.02 (SD 1.95) with metformin (between groups p = .714) (Figure 2a). However, metformin prevented gains in lean mass with PRT (between groups p = .003); placebo gained 1.95% (SD 2.69) lean mass (p < .001), while the 0.41% change (SD 2.25) in metformin did not reach significance (p = .218) (Figure 2b; Appendix S2: Table 2). Metformin also blocked thigh muscle mass gains (between groups p < .001), with placebo gaining 3.90% (SD 5.54) (p < .001), and metformin showing no significant gain (0.45%, SD 3.95) (p = .441) (Figure 2c; Appendix S2: Table 2).
Figure 2
Metformin does not affect decreases in percent fat, but blunts gains in lean mass and thigh muscle mass following PRT. Body composition and bilateral thigh muscle mass were measured using DXA. N = 48 placebo, 46 metformin. (a) With PRT, percent fat was reduced in most participants, and this reduction was not affected by metformin (p = .714). (b) Percent change in lean mass was larger in placebo than in metformin (p = .003), and © percent change in thigh muscle mass was also larger in placebo than in metformin (p < .001). Student's t test. Box plots indicate the mean (×) and median (‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐), and whiskers indicate the upper and lower quartiles.
With PRT, increases in strength tended to be lower with metformin, but differences were not statistically significant (Table 2). Knee extension 1 repetition maximum (RM) increased 23.1% (SD 18.9) in placebo and 15.3% (SD 18.5) in metformin (between groups p = .055); knee extension isometric strength increased 11.8% (SD 12.7) with placebo compared to 6.7% (SD 14.5) with metformin (between groups p = .082); and peak knee extension power increased 29.4% (SD 40.7) in placebo versus 14.3% (SD 35.7) in metformin (between groups p = .064). Relative strength (knee extension kg/bilateral thigh muscle mass kg) gains following PRT were similar in both groups, with placebo improving 19.7% (SD 19.0) and metformin improving 14.5% (SD 17.9) (between groups p = .188).
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