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Spinal muscular atrophy (SMA) is a rare, genetic neurodegenerative disorder caused by insufficient production of survival motor neuron (SMN) protein. Diminished SMN protein levels lead to motor neuron loss, causing muscle atrophy and weakness that impairs daily functioning and reduces quality of life. SMN upregulators offer clinical improvements and increased survival in SMA patients, although significant unmet needs remain. Myostatin, a TGF-β superfamily signaling molecule that binds to the activin II receptor, negatively regulates muscle growth; myostatin inhibition is a promising therapeutic strategy for enhancing muscle. Combining myostatin inhibition with SMN upregulation, a comprehensive therapeutic strategy targeting the whole motor unit, offers promise in SMA. Taldefgrobep alfa is a novel, fully human recombinant protein that selectively binds to myostatin and competitively inhibits other ligands that signal through the activin II receptor. Given a robust scientific and clinical rationale and the favorable safety profile of taldefgrobep in patients with neuromuscular disease, the RESILIENT phase 3, randomized, placebo-controlled trial is investigating taldefgrobep as an adjunct to SMN upregulators in SMA (NCT05337553). This manuscript reviews the role of myostatin in muscle, explores the preclinical and clinical development of taldefgrobep and introduces the phase 3 RESILIENT trial of taldefgrobep in SMA.

Evolutionary pressures to protect against food scarcity likely resulted in highly-conserved pathways designed to minimize energy expenditure, one of which involves the minimization of muscle mass; these mechanisms may be counter-productive in a modern world suffering from obesity and sarcopenia. Growth differentiation factor 8 (GDF8)/myostatin, acting via ActRIIA/B receptors, is the best-characterized negative regulator of muscle mass, leading to therapeutic efforts to augment muscle growth by blocking GDF8 or ActRIIA/B. ActRIIA/B blockade approximately doubles the muscle increase of GDF8 blockade, and as ActRIIA/B responds to multiple other TGFβ-family members, this implies other ligands might also regulate muscle mass. Previously, we suggested that activin A (ActA) is the key second negative regulator acting via ActRIIA/B, as blockade of both GDF8 and ActA in mice/monkeys matches the muscle growth of ActRIIA/B blockade. Here, we extend these observations to humans in a two-part, randomized, placebo-controlled Phase 1 trial ( www.clinicaltrials.gov , NCT02943239) conducted at two sites in New Zealand. Eligible subjects included healthy postmenopausal females aged 45–70 years and males aged 35–60 years not intending to father children, with a body mass index of 18–32 kg/m 2 . Part I tested single-dose administration of anti-GDF8 alone, anti-ActA alone, several dose combinations of anti-GDF8 + anti-ActA, or placebo in healthy postmenopausal females; part II tested multiple-dose administration of anti-ActA alone or placebo in healthy postmenopausal females, combination anti-GDF8 + anti-ActA or placebo in healthy postmenopausal females, and anti-ActA alone or placebo in healthy males. The primary outcome measure was the incidence and severity of treatment-emergent adverse events through week 16 for the single-dose part of the study and through week 40 for the multiple-dose part of the study. Secondary endpoints included percent and absolute change in thigh muscle volume, percent and absolute change in total and regional body composition, pharmacokinetic profiles of the GDF8 and ActA mAbs in serum over time, changes in serum total GDF8 and total ActA levels over time, and the presence of anti-drug antibodies against the GDF8 mAb or the ActA mAb. Magnetic resonance imaging was used to quantitate changes in thigh muscle volume and dual x-ray absorptiometry was used to quantitate changes in regional body composition (total lean mass, appendicular lean body mass, android fat mass, and total fat mass). A total of 82 subjects were enrolled (48 in the single-dose part and 34 in the multiple-dose part of the study). Baseline demographic and clinical characteristics were generally balanced across the single- and multiple-dose parts of the study. Combining GDF8 and ActA blocking antibodies led to greater muscle growth than either antibody alone; increases in muscle were accompanied by reductions in fat. The observed clinical effects on muscle and fat paralleled mAb exposure in serum. The combination was generally well tolerated, and no subjects tested positive for anti-drug antibodies post-treatment. These results suggest that GDF8 and ActA are the dominant negative regulators of muscle mass in humans, and that combined blockade may be a promising therapeutic approach in muscle atrophy and obesity settings. GDF8 and activin A are the dominant negative regulators of muscle mass in animal models. This two-part, randomized, placebo-controlled Phase 1 trial suggests that GDF8 and activin A are also the dominant negative regulators of muscle mass in humans.

Clinical trials with treatments inhibiting myostatin pathways to increase muscle mass are currently ongoing in spinal muscular atrophy. Given evidence of potential myostatin pathway downregulation in Spinal Muscular Atrophy (SMA), restoring sufficient myostatin levels using disease-modifying treatments (DMTs) might arguably be necessary prior to considering myostatin inhibitors as an add-on treatment. This retrospective study assessed pre-treatment myostatin and follistatin levels’ correlation with disease severity and explored their alteration by disease-modifying treatment in SMA. We retrospectively collected clinical characteristics, motor scores, and mysotatin and follistatin levels between 2018 and 2020 in 25 Belgian patients with SMA (SMA1 (n = 13), SMA2 (n = 6), SMA 3 (n = 6)) and treated by nusinersen. Data were collected prior to treatment and after 2, 6, 10, 18, and 30 months of treatment. Myostatin levels correlated with patients’ age, weight, SMA type, and motor function before treatment initiation. After treatment, we observed correlations between myostatin levels and some motor function scores (i.e., MFM32, HFMSE, 6MWT), but no major effect of nusinersen on myostatin or follistatin levels over time. In conclusion, further research is needed to determine if DMTs can impact myostatin and follistatin levels in SMA, and how this could potentially influence patient selection for ongoing myostatin inhibitor trials.

Background: Recently, many studies have been devoted to discovering nutrients for exercise-like effects. Resistance exercise and the intake of essential amino acids (EAAs) are known to be factors that can affect muscle mass and strength improvement. The purpose of this study was to investigate changes in muscle quality, myokines, and inflammation in response to resistance exercise and EAA supplementation. Methods: Thirty-four males volunteered to participate in this study. They were assigned to four groups: (1) placebo (CO), (2) resistance exercise (RE), (3) EAA supplementation, and (4) RE + EAA supplementation. Body composition, muscle quality, myokines, and inflammation were measured at baseline and four weeks after treatment. Results: Lean body fat had decreased in both RE and RE + EAA groups. Lean body mass had increased in only the RE + EAA group. In all groups except for CO, irisin, myostatin A, and TNF-α levels had decreased. The grip strength of the right hand and trunk flexion peak torque increased in the RE group. The grip strength of the left hand, trunk flexion peak torque, and knee flexion peak torque of the left leg were increased in RE + EAA. Conclusions: RE, EAA, and RE + EAA could effectively improve the muscle quality, myokine, and inflammation factors of young adult males. This finding highlights the importance of resistance exercise and amino acid intake.

Impaired iron metabolism is associated with increased risk of many morbidities. Exercise was shown to have a beneficial role; however, the mechanism is not well understood. The purpose of this study was to assess the relationship between exerkines and iron metabolism in elderly women before and after 12 weeks of Nordic Walking (NW) training. Exerkines like myostatin, adiponectin, and osteocalcin have been shown to have several positive effects on metabolism. Thirty-six post-menopausal women (66 ± 5 years old, mean ± SD) were randomly assigned to a NW intervention group (n = 18; body mass, 68.8 ± 11.37 kg; fat, 23.43 ± 7.5 kg; free fat mass, 45.37 ± 5.92 kg) or a control group (n = 18; body mass, 68.34 ± 11.81 kg; fat, 23.61 ± 10.03 kg; free fat mass, 44.73 ± 3.9 kg). The training was performed three times a week for 12 weeks, with the intensity adjusted to 70% of the individual maximum ability. Before and one day after the 12-weeks intervention, performance indices were assessed using a senior fitness test. Blood samples (5 mL) were obtained from the participants between 7 and 8 AM, following an overnight fast, at baseline and one day immediately after the 12-week training program. A significant and large time × group interaction was observed for iron (NW: 98.6 ± 26.68 to 76.1 ± 15.31; CON: 100.6 ± 25.37 to 99.1 ± 27.2; p = 0.01; η p 2 = 0.21), myostatin (NW: 4.42 ± 1.97 to 3.83 ± 1.52; CON: 4.11 ± 0.95 to 4.84 ± 1.19; p = 0.00; η p 2 = 0.62), adiponectin (NW: 12.0 ± 9.46 to 14.6 ± 10.64; CON: 12.8 ± 8.99 to 11.9 ± 8.53; p = 0.00; η p 2 = 0.58), and osteocalcin (NW: 38.9 ± 26.04 to 41.6 ± 25.09; CON: 37.1 ± 33.2 to 37.2 ± 32.29; p = 0.03; η p 2 = 0.13). Furthermore, we have observed the correlations: basal ferritin levels were inversely correlated with changes in myostatin (r = −0.51, p = 0.05), change in adiponectin, and change in serum iron (r = −0.45, p = 0.05), basal iron, and osteocalcin after training (r = -0.55, p = 0.04). These findings indicate that iron modulates NW training-induced changes in exerkine levels.

Delayed onset muscle soreness (DOMS) due to intense physical exertion can negatively impact contractility and performance. Previously, NPN_1 (PeptiStrong™), a Vicia faba hydrolysate derived from a protein concentrate discovered through artificial intelligence (AI), was preclinically shown to help maintain muscle health, indicating the potential to mediate the effect of DOMS and alter molecular markers of muscle damage to improve recovery and performance. A randomised double-blind placebo-controlled trial was conducted on 30 healthy male (30–45 years old) volunteers (NCT05159375). Following initial strength testing on day 0, subjects were administered either placebo or NPN_1 (2.4 g/day). On day 14, DOMS was induced using resistance exercise. Strength recovery and fatigue were measured after 48 and 72 h. Biomarker analysis was performed on blood samples collected prior to DOMS induction and 0, 2, 48 and 72 h post-DOMS induction. NPN_1 supplementation significantly improved strength recovery compared to placebo over the 72 h period post-resistance exercise (p = 0.027), measured by peak torque per bodyweight, but not at individual timepoints. Muscle fatigue was significantly reduced over the same 72 h period (p = 0.041), as was myostatin expression (p = 0.006). A concomitant increase in other acute markers regulating muscle protein synthesis, regeneration and myoblast differentiation was also observed. NPN_1 significantly improves strength recovery and restoration, reduces fatigue and positively modulates alterations in markers related to muscle homeostasis.

To evaluate the effect of L-carnitine (LC) in combination with leucine supplementation on muscle strength and muscle hypertrophy in aged women participating in a resistance exercise training (RET) program. Thirty-seven out of sixty (38.3% dropout) healthy women aged 60–75 years (mean 67.6 ± 0.7 years) completed the intervention in one of three groups. One of the supplemented groups received 1 g of L-carnitine-L-tartrate in combination with 3 g of L-leucine per day (LC+L group; n = 12), and the second supplemented group received 4 g of L-leucine per day (L group; n = 13). The control group (CON group; n = 12) received no supplementation. All three groups completed the same RET protocol involving exercise sessions twice per week for 24 weeks. Before and after the experiment, participants performed isometric and isokinetic muscle strength testing on the Biodex dynamometer. The cross-sectional areas of the major knee extensors and total thigh muscles were assessed using magnetic resonance imaging. Fasting serum levels of insulin-like growth factor-1 (IGF-1), myostatin and decorin, and plasma levels of total carnitine (TC) and trimethylamine-N-oxide (TMAO) levels were measured. The 24-week RET significantly increased muscle strength and muscle volume, but the group and time interactions were not significant for the muscle variables analyzed. Plasma total carnitine increased only in the LC+L group (p = 0.009). LC supplementation also caused a significant increase in plasma TMAO, which was higher after the intervention in the LC+L group than in the L (p < 0.001), and CON (p = 0.005) groups. The intervention did not change plasma TMAO concentration in the L (p = 0.959) and CON (p = 0.866) groups. After the intervention serum decorin level was higher than before in both supplemented groups combined (p = 0.012), still not significantly different to post intervention CON (p = 0.231). No changes in serum IGF-1 and myostatin concentrations and no links between the changes in blood markers and muscle function or muscle volume were observed. LC combined with leucine or leucine alone does not appear to improve the effectiveness of RET.

The effects of timed ingestion of high-quality protein before and after resistance exercise are not well known. In this study, young men were randomized to protein (n = 11), placebo (n = 10) and control (n = 10) groups. Muscle cross-sectional area by MRI and muscle forces were analyzed before and after 21 weeks of either heavy resistance training (RT) or control period. Muscle biopsies were taken before, and 1 and 48 h after 5 × 10 repetition leg press exercise (RE) as well as 21 weeks after RT. Protein (15 g of whey both before and after exercise) or non-energetic placebo were provided to subjects in the context of both single RE bout (acute responses) as well as each RE workout twice a week throughout the 21-week-RT. Protein intake increased (P ≤ 0.05) RT-induced muscle cross-sectional area enlargement and cell-cycle kinase cdk2 mRNA expression in the vastus lateralis muscle suggesting higher proliferating cell activation response with protein supplementation. Moreover, protein intake seemed to prevent 1 h post-RE decrease in myostatin and myogenin mRNA expression but did not affect activin receptor IIb, p21, FLRG, MAFbx or MyoD expression. In conclusion, protein intake close to resistance exercise workout may alter mRNA expression in a manner advantageous for muscle hypertrophy.

Although transcriptome profiling has been used in several resistance training studies, the associated analytical approaches seldom provide in-depth information on individual genes linked to skeletal muscle hypertrophy. Therefore, a secondary analysis was performed herein on a muscle transcriptomic dataset we previously published involving trained college-aged men (n = 11) performing two resistance exercise bouts in a randomized and crossover fashion. The lower-load bout (30 Fail) consisted of 8 sets of lower body exercises to volitional fatigue using 30% one-repetition maximum (1 RM) loads, whereas the higher-load bout (80 Fail) consisted of the same exercises using 80% 1 RM loads. Vastus lateralis muscle biopsies were collected prior to (PRE), 3 h, and 6 h after each exercise bout, and 58 genes associated with skeletal muscle hypertrophy were manually interrogated from our prior microarray data. Select targets were further interrogated for associated protein expression and phosphorylation induced-signaling events. Although none of the 58 gene targets demonstrated significant bout x time interactions, ~57% (32 genes) showed a significant main effect of time from PRE to 3 h (15↑ and 17↓, p < 0.01), and ~26% (17 genes) showed a significant main effect of time from PRE to 6 h (8↑ and 9↓, p < 0.01). Notably, genes associated with the myostatin (9 genes) and mammalian target of rapamycin complex 1 (mTORC1) (9 genes) signaling pathways were most represented. Compared to mTORC1 signaling mRNAs, more MSTN signaling-related mRNAs (7 of 9) were altered post-exercise, regardless of the bout, and RHEB was the only mTORC1-associated mRNA that was upregulated following exercise. Phosphorylated (phospho-) p70S6K (Thr389) (p = 0.001; PRE to 3 h) and follistatin protein levels (p = 0.021; PRE to 6 h) increased post-exercise, regardless of the bout, whereas phospho-AKT (Thr389), phospho-mTOR (Ser2448), and myostatin protein levels remained unaltered. These data continue to suggest that performing resistance exercise to volitional fatigue, regardless of load selection, elicits similar transient mRNA and signaling responses in skeletal muscle. Moreover, these data provide further evidence that the transcriptional regulation of myostatin signaling is an involved mechanism in response to resistance exercise.

Background. In this study we investigated the relevance of myostatin and Hepatocyte Growth Factor (HGF) in patients undergoing hemodialysis HD and the influence of different HD modalities on their levels. Methods. We performed a prospective crossover study in which HD patients were randomized to undergo 3-month treatment periods with bicarbonate hemodialysis (BHD) followed by online hemodiafiltration (HDF). Clinical data, laboratory parameters, and myostatin and HGF serum levels were collected and compared. Results. Ten patients and six controls (C) were evaluated. In any experimental condition myostatin and HGF levels were higher in HD than in C. At enrollment and after BHD there were not significant correlations, whereas at the end of the HDF treatment period myostatin and HGF were inversely correlated (r -0.65, p<0.05), myostatin serum levels inversely correlated with transferrin (r -0.73, p<0.05), and HGF levels that resulted positively correlated with BMI (r 0.67, p<0.05). Moving from BHD to HDF, clinical and laboratory parameters were unchanged, as well as serum HGF, whereas myostatin levels significantly decreased (6.3 ± 4.1 versus 4.3 ± 3.1 ng/ml, p<0.05). Conclusions. Modulation of myostatin levels and myostatin/HGF balance by the use of different HD modalities might represent a novel approach to the prevention and treatment of HD-related muscle wasting syndrome.