The participant and his parents signed a written informed consent form before his inclusion in the study. The patient’s clinical history highlighted fundamental critical episodes. In 2012 a serum hyperCKemia (around 1,500 U/L) was measured in the emergency room following a car accident. Considering that hyperCKemia can be associated with CCM (Topaloglu, 2020), further CK measurements were recommended to tell if this incidental evidence had to be attributed to the underlying disease or to the car accident, confirming that these abnormal values were the norm for the patient. Therefore, since this event, periodical CK investigations were performed to keep the parameter under observation. In February 2023 a marked increase in serum CK (7604 U/L) was found 2 days after at home unsupervised physical activity as follows: 1) the activity was performed every day for 6 days; 2) the total duration of each exercise session was 25–30 min; 3) the activity was alternated: 1 day biking, 1 day body weight resistance training with squat and plank paradigms (approximately 30 s per exercise); 4) on the second day, delayed onset muscle soreness (DOMS) appeared and persisted in the following 7 days; 5) to retrospectively quantify the perceived effort at the end of each session, the Borg category ratio (CR) 0–10 scale (Borg, 1982) was used, given its proven effectiveness in quantifying effort in both resistance training (Hiscock et al., 2015; Morishita et al., 2019) and aerobic training (Marinov and Kostianev, 2003; Yáñez-Sepúlveda et al., 2018). The value reported by the subject was eight for each session. These data were subsequently considered to tailor the training program.

In March 2023, we aimed to find a safe and effective strategy to incorporate combined aerobic and resistance exercise into the patient’s life in an attempt to counteract the progression of disease. Suchchoice was based upon the documented role of aerobic and resistance exercise in preserving muscle structure and function in both healthy (Egan and Zierath, 2013) and diseased muscle (Voet et al., 2019; Parimbelli et al., 2021; Crisafulli et al., 2022). The following descripted methodologies are part of the clinical procedures habitually adopted in our sport medicine centre. Notably, we usually apply such paradigms in patients with other myopathies at risk of rhabdomyolysis, such as metabolic myopathies. To safely provide a tailored training program, adapted from the independent physical activity reported by the patient, the subject underwent a 3-week (one exercise session per week) preliminary tolerance test in which exercise intensity was reduced (Borg 8→Borg 6) and duration was maintained (25 min) as follows: week 1, aerobic training on a bike alternating 2 min at Borg 4 (heart rate range, 117–127 bpm) and 1 min at Borg 6 (heart rate range, 135–150 bpm), the training was carried out with the use of a heart rate monitor; week 2, resistance training including exercises for core and abdominal muscle [hand-foot plank, front plank (2 sets for 30 s each) crunch and reverse bent leg crunch (2 sets of 15 rep each)], lower limbs [squat, two-legged and single-legged calf standing, climb a step with weight (3 sets of 12 reps each)] and upper limbs including the shoulders (overhead press, lateral raises), and triceps and pectorals muscle (push-ups) (2 sets of 12 reps each). In this session, exercises were interspersed with 2 min recovery and performed without emphasizing the eccentric phase of the contraction, known as potential cause of rhabdomyolysis (Heled et al., 2005); week 3, mixed aerobic [10 min of bike alternating 2 min at Borg 4 (heart rate range, 117–127 bpm) and 1 min at Borg 6], and resistance training (repeating week 2 session removing 1 set and 2 repetitions from each exercise). All sessions were supervised by a qualified operator (MV) for patient safety and to ensure compliance with the proposed program.

Thirty-six hours following each exercise session, a blood sample was collected to measure circulating CK levels. For 1 week after each session, a daily quantification of soreness was obtained by means of the visual analogue scale (VAS), commonly used to quantify DOMS (Dannecker et al., 2003; Gast et al., 2023). DOMS peak value and duration were reported.

At the completion of the 3-week preliminary tolerance test, the resulting CK and DOMS measures were as follows: week 1, CK = 1343 U/L, DOMS duration (days) = 0, DOMS peak = 0; week 2, CK = 1145 U/L, DOMS duration (days) = 1, DOMS peak = 1 (1 day after test); week 3 (mixed aerobic and resistance training), CK = 1377 U/L, DOMS duration (days) = 1, DOMS peak = 1 (1 day after test).

The training program included resistance exercises twice a week and aerobic exercises once a week, which were carried out with the same modalities of the preliminary test but with less rest days between the sessions (from 7 days to 2 days). The weekly frequency of the sessions (3 per week) was chosen considering that 36 h after the preliminary training sessions, time frame within which, considering the moderate intensity of the exercises, serum CK should have reached its peak (Clarkson et al., 1992), the CK values were comparable to those found in some previous routine checks (Figure 2), suggesting a possible cumulative effect as unlikely. Moreover, the reported modest duration and degree of DOMS, indicated the reasonable possibility of good tolerability of the proposed workload, without inducing exercise-related pain or discomfort. The training program lasted 3 months as it is a time frame widely sufficient to induce adaptations to both resistance (Damas et al., 2018) and aerobic training (Matsuo et al., 2014; Duarte et al., 2023). Stretching followed each training session to prevent contractures and strains (Harvey and Herbert, 2002; Nunes et al., 2020) which, given the predisposition dictated by the disease (Lawal et al., 2020), could likely have occurred. As during the preliminary test, all sessions were carried out under supervision.

Before and after the training program, the patient underwent a battery of metabolic and cardiopulmonary tests. Resting metabolic rate (RMR) was measured at 08.00 h in a room where ambient temperature was fix at 23°C using indirect calorimetry technique (Quark PFT, Cosmed, Italy). The patient arrived in a fasted state (from 8 h) and was instructed to lie quietly for 10 min, after which a ventilated hood was placed over the head (Canopy, Cosmed, Italy). The subject was asked to relax but remain awake for the duration of the test (25 min). The dilution rate was adjusted during the first 5 min of the test so the fraction of expired VCO₂ was between 1.0% and 1.2%. This portion of the test was excluded to allow breathing and dilution rate to normalize; RMR and RQ were averaged over the remaining 20 min. Initial RMR was 1,588 kcal/day, with an RQ of 0.76 (normal range at rest 0.7–0.85) (Guthrie et al., 1964), highlighting a high percentage of fat utilization (83%).

Bioimpedance (Akern, Pontassieve, Italy) was utilized to evaluate body composition through the measurement of its impedance consisting of resistance (R) and reactance (Xc). The following parameters were measured: muscle mass (MM), body cell mass (BCM), fat mass (FM) and phase angle (PA, 6) measured as [arctangent (Xc/R) × 180°/π]. For the measurement of MM, BCM and FM values, bioimpedance uses predictive equations that have not been validated in this type of patient and could, therefore, be altered by over- or underestimation errors (Kyle et al., 2004; Beaudart et al., 2020). For this reason, considering that the bias, if present, would be constant, the pre and post training evaluation relating to these parameters is proposed only as the difference between the values obtained before and after the intervention (see Table 1).

A cardiopulmonary exercise test (CPET) was performed on a cycloergometer (E 100, Cosmed, Italy), with the patient wearing a two-way breathing mask covering the nose and mouth (V2 Mask TM, Hans Rudolph Inc., United States), connected to a gas analyzer (Quark PFT, Cosmed, Italy). CPET was performed with an incremental technique (15 W every 2 min, with a previous warm up of 5 min at 20 W), and VO₂ and VCO₂ output were measured using the breath-by-breath method. The test was performed until exhaustion, with the achievement of a respiratory exchange ratio (RER) of 1.15 (>1.1 maximal effort index), a blood lactate value of 10 mmol/L and a Borg CR 10 value of 10. For blood lactate determination, blood sample was obtained from the earlobe and concentration was determined by a specific lactate detection device (Lactate Pro 2, Arkray, Kyoto, Japan). Ventilatory anaerobic threshold (VAT) was assessed from the slopes of VO₂ and VCO₂.

VO₂ max was 1,703 mL/min corresponding to 31.9 mL/min/kg (normal range for age and gender over 1,933 mL/min or over 24.8 mL/min/kg). Overall CPET underlined a very low oxygen uptake during the effort, not from respiratory deficiency, as VE/VCO₂ was below 30, but from the mitochondrial metabolic impairment. All the pre- and post-training program values are reported in Table 1. Coherently with the preliminary tolerance test procedure, post-training program CK measurement was performed 36 hours after the last exercise session (Figure 2).

To plan an adequate nutritional support to the training program, a qualified team led by an experienced dietitian (EL) assessed the nutritional status of the patient by using diagnostic-clinical tools including the evaluation of the dietary intake (macronutrients, micronutrients and energy intake), blood biochemical analysis, and anthropometrical and body composition determinations (Taberna et al., 2019). The patient’s long-term diet was assessed by using the Quantitative Food-frequency Questionnaire (FFQ) on a typical week from which three non-consecutive days were extrapolated (Yang et al., 2010). The nutritional intake adequacy was then analysed based on the Recommended Levels of Nutrients and Energy Intakes (LARN) (Sinu, 2023). Energy intake and macronutrient distribution resulted inadequate to satisfy the needs (3,130 kcal/day; CHO 43%, FAT 35%, daily proteins 107.13 gr). An elevated consumption of saturated fats was also found. Blood biochemical evaluation revealed vitamin C (4.3 mg/L), vitamin D (23.6 ug/L) and Cu (60 ug/dL) deficiencies.

Considering a RMR of 1,588 kcal/day (Table 1), a personalized isocaloric Mediterranean diet of 2,000 kcal/day was determined based on the estimated calorie needs per day, by age and gender in patients with neuromuscular disorders (Burgos et al., 2018). The daily diet was tailored to reach a macronutrient intake of 50% CHO, 30% FAT, and a protein intake of 1.5 g/kg body weight/day in accordance with nutritional recommendations for the management of sarcopenia (Rogeri et al., 2021). In addition, the patient began a regimen of nutritional supplementation to sustain protein synthesis (Aminotrofic, Errekappa, 7 g/day of essential amino acid mixture) and to adjust the identified vitamin deficiencies (multivitamin Unicomplex Plus, Kline, 2 sachets/die). This nutritional regimen was maintained all throughout the training program and the compliance was assessed via a diary in which the patient had to record the food consumed. Before every third training session of the week, the diary was checked by one of the researchers responsible for the nutritional plan (JL, EL, MN, SA).